General method for the preparation of active esters by palladium-catalyzed alkoxycarbonylation of aryl bromides

Article abstract of DOI:10.1021/jo5025464

A useful method was developed for the synthesis of active esters by palladium-catalyzed alkoxycarbonylation of (hetero)aromatic bromides. The protocol was general for a range of oxygen nucleophiles including N-hydroxysuccinimide (NHS), pentafluorophenol (PFP), hexafluoroisopropyl alcohol (HFP), 4-nitrophenol, and N-hydroxyphthalimide. A high functional group tolerance was displayed, and several active esters were prepared with good to excellent isolated yields. The protocol was extended to access an important synthetic precursor to the HIV-protease inhibitor, saquinavir, by formation of an NHS ester followed by acyl substitution.

Full text of DOI:10.1021/jo5025464

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Note
A General Method for the Preparation of Active Esters by
Palladium Catalyzed Alkoxycarbonylation of Aryl Bromides
Angelina M. de Almeida, Thomas L. Andersen, Anders T.
Lindhardt, Mauro V. De Almeida, and Troels Skrydstrup
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5025464 • Publication Date (Web): 07 Jan 2015
Downloaded from http://pubs.acs.org on January 12, 2015
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The Journal of Organic Chemistry
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A General Method for the Preparation of Active Esters by Palladium
Catalyzed Alkoxycarbonylation of Aryl Bromides.
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†
Angelina M. de Almeida,‡,§ Thomas L. Andersen,§ Anders T. Lindhardt, * Mauro V. de Almeida, ‡ and Troels
Skrydstrup§*
§The Center for Insoluble Protein Structures (inSPIN), Department of Chemistry and the Interdisciplinary
Nanoscience Center, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus, Denmark.
† Department of Engineering, Aarhus University, Finlandsgade 22, 8200 Aarhus N, Denmark.
‡Department of Chemistry, Federal University of Juiz de Fora, Campus Martelos, Juiz de Fora, MG 36036ꢀ330,
Brazil.
lindhardt@eng.au.dk, ts@chem.au.dk
ABSTRACT: A useful method was developed for the synthesis of active esters by palladium-catalyzed
alkoxycarbonylation of (hetero)aromatic bromides. The protocol was general for a range of oxygen
nucleophiles including N-hydroxysuccinimide (NHS), pentafluorophenol (PFP), hexafluoroisopropanol
(HFP), 4-nitrophenol and N-hydroxyphthalimide A high functional group tolerance was displayed and
several active esters were prepared with good to excellent isolated yields. The protocol was extended to
access an important synthetic precursor to the HIV-protease inhibitor, saquinavir, by formation of an NHS-
ester followed by acyl substitution.
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The use of active esters as coupling partners in acyl substitution reactions is a predominant strategy
throughout the field of organic synthesis, and it is equally important in Nature, whereby e.g. acetylꢀ
CoA serves as a widespread acetylating agent. By this method, a carboxylic acid can be converted into
an acylating agent and the formation of C–O, C–N and, C–S bonds is easily achieved by subsequent
acyl substitution. Active esters have found widespread use in the synthesis of natural products,1ꢀ3
pharmaceuticals,4 synthetic peptides,5,6 and also to a large extent as crosslinking reagents in
bioconjugation.7 Many methods for the activation of carboxylic acids have been developed, including
direct activation with strong acids (Fischer esterification), conversion into acid halides with e.g. SOCl2
or cyanuric acid, conversion into either mixed or symmetric anhydrides, Steglich type carbodiimide
activation (EDC, DCC) often in combination with coupling additives (HOBt, HOAt),8,9 and treatment
with phosphonium salts, and others.10 However, all of these approaches require the presence or preꢀ
installment of the carboxylic acid moiety, which, besides additional synthetic manipulation, may be
inconvenient or even absent. Therefore, the transformation of alternative functionalities other than
carboxylic acids directly into an active ester is a desirable and equally efficient method. To this end,
recent developments have been focused on the direct oxidative transformation of aldehydes into
amides and esters11,12 and in a one example, the transformation of aldehydes directly into isolable
active esters has been reported.13
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In 2003, a Pdꢀcatalyzed carbonylation strategy for the preparation of Nꢀhydroxysuccinimido esters
was presented by Lou et al.14 In this work, a selection of aryl iodides and aryl triflates were coupled to
Nꢀhydroxysuccinimide (NHS) in the presence of carbon monoxide (CO). Bromobenzene was also
employed as the electrophile but resulted in a mere 26% isolated yield of the desired NHSꢀester. A
carbonylative strategy towards activated esters is highly appealing due to the elaborate literature on
the formation of sp2 carbonꢀhalogen bonds, such as electrophillic aromatic substitution or Sandmeyer
type transformations, rendering highly functionalized aromatic halides readily available. Furthermore,
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the combination of these starting materials with a mild and selective Pdꢀcatalyzed carbonylative
protocol provides facile access to activated esters.15
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In this context, we herein present an efficient and general method for the preparation of active esters
by a Pdꢀcatalyzed alkoxycarbonylation of aromatic and heteroaromatic bromides. The scope of this
methodology includes active esters formed from Nꢀhydroxysuccinimide 1a (NHS), pentafluorophenol
1b, hexafluoroisopropyl alcohol 1c, pꢀnitrophenol 1d and Nꢀhydroxyphthalimide 1e¸which were all
found to be excellent coupling partners (Scheme 1) under the developed conditions. This extension of
the Pdꢀcatalyzed alkoxycarbonylation is not obvious, owing to the lowered nucleophilicity of the
employed coupling partners when compared to more classic alcohols. Finally, the method was
employed to generate an established precursor to the antiretroviral drug, saquinavir, and its 13Cꢀ
isotope analog.
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Scheme 1. Formation of Active Esters by Pd-Catalyzed Alkoxycarbonylation of Aryl Bromides
As a starting point, the test reaction of 4ꢀbromoanisole with NHS as the nucleophile was chosen.
Based on preliminary work performed by the group of Beller, [Pd(cinnamyl)Cl]2 was chosen as the
catalyst precursor in combination with toluene as the solvent.16 All experiments were carried out using
the previously reported COware/COgen twoꢀchamber technique.17,18 Initial testing of various monoꢀ
and bidentate ligands including dppf, DiPrPF, BINAP, PPFꢀtBu and PPh3, all but one providing low
rates of conversion (Tabe 1, entries 1ꢀ5). Although, PPh3 did provide full conversion, it was decided to
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seek out ligands of higher oxidative addition potential to avoid downstream problems with more
complicated electrophiles. The ligands, HBF4PtBu3 and Xantphos, led to more optimal turnovers and
product distributions as both ligands provided full conversion of the starting bromide and 73% and
88% isolated yields were obtained of the NHSꢀester 2a, respectively (Table 1, entries 6 and 7). A
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closer inspection of the HꢀNMR spectra of the crude reaction mixture from the reaction applying
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Xantphos, revealed the formation of 3a (entry 6). We propose the origin of 3a to be an aryl exchange
reaction between a phenyl group of the phosphine ligand and the arylꢀPd(II)ꢀBr complex formed after
oxidative addition.19,20,21 Applying HBF4PtBu3 as the ligand, lacking phenyl substituents, did clearly
not lead to the formation of 3a as a byproduct and was therefore chosen (entry 7). The same selectivity
and high catalytic activity was maintained even when the nucleophileꢀ and COꢀloading were lowered
to 1.05 equiv. and 1.2 equiv., respectively (entries 8 and 9). Attempts to lower the loading of the
[Pd(cinnamyl)Cl]2/HBF4PtBu3 catalytic system led to incomplete conversion and no further iterations
of the conditions were attempted. Finally, an experiment was conducted in which the peak partial
pressure of CO was increased to 3.7 bar (total peak pressure of 4.7 bar in the COware system) but
only a 50 % conversion was obtained (entry 10). The result in entry 10 indicates that an increased COꢀ
pressure impedes the catalytic efficiency of this alkoxycarbonylation.
Table 1. Key Entries in the Optimization of the PdꢀCatalyzed Alkoxycarbonylation of Aryl Bromides
with NꢀHydroxysucciniimidea
Conversionb
(Yield%)c
42 %
2a : 3ab
100 : 0
100 : 0
100 : 0
100 : 0
Entry
NHS (equiv)
Ligand
1
1.4
DiPrPF
2
3
4
1.4
1.4
1.4
DPPF
82 %
48 %
48 %
racꢀBINAP
PPFꢀtBu
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d
100 : 0
80:20
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1.4
1.4
PPh3
100 %
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8
Xantphos
HBF4PtBu3
HBF4PtBu3
HBF4PtBu3
HBF4PtBu3
100 % (73 %)
100 % (88 %)
100 %
100 : 0
100 : 0
100 : 0
100 : 0
7
1.4
8
1.05
1.05
1.05
9e
10f
100 % (88%)
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50 %
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b
1
aFull experimental details are described in the Supporting Information. As determined from the H
c
d
e
NMR spectrum of the crude reaction mixture. Isolated yield of 2a. 12 mol % of PPh3. COgen (1.2
equiv). 3.7 bars of COꢀpressure applied. DiPrPF: 1,1′ꢀbis(diisopropylphosphino)ferrocene DPPF:
1,1′ꢀbis(diphenylphosphino)ferrocene, racꢀBINAP: 2,2′ꢀBis(diphenylphosphino)ꢀ1,1′ꢀbinaphthalene
PPFꢀtBu: (R)ꢀ1ꢀ[(SP)ꢀ2ꢀ(Diphenylphosphino)ferrocenyl]ethyldiꢀtertꢀbutylphosphine, Xantphos: 4,5ꢀ
(diphenylphosphino)ꢀ9,9ꢀdimethylxanthene, HBF4PtBu3: triꢀtertꢀbutylphophonium tetrafluoroborate.
f
Having established an efficient catalytic system for the formation of NHSꢀesters, we proceeded to
test the generality of this system with a range of different aryl bromides. Initially, electronꢀrich aryl
bromides were examined, providing substrates 5a, 12a, 13a, 18a, and 19a in yields ranging from 64–
95% (Scheme 2).
Scheme 2. Pd-Catalyzed Alkoxycarbonylation of Aryl Bromides to Produce NHS-Estersa
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CO (1.2 equiv)
[{Pd(cinnamyl)Cl}2] (3 mol %)
HBF4PtBu3(6 mol%)
Cy2NMe (1.5 equiv)
O
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2
3
4
O
O
C
(Het)Ar
Br
+
N
N
OH
(Het)Ar
O
O
Toluene, 95 oC, 16 h
O
1a (1.05 equiv)
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O
O
O
O
O
O
C
O
C
O
C
N
N
N
C
N
O
O
O
O
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O
O
O
O
F
nBu
NC
88% ꢀ 3a
80% ꢀ 4a
75% ꢀ 5a
72% ꢀ 6a
O
O
O
O
O
O
O
O
C
N
C
N
C
N
C
N
O
O
O
O
O
O
O
O
MeO
Ph
BocHN
84% ꢀ 7a
78% ꢀ 8a
89% ꢀ 9a
82% ꢀ 10a
O
OMe
O
O
O
O
O
O
O
O
F3C
C
N
C
N
MeO
MeO
C
N
C
N
O
O
O
O
O
O
O
O
90% ꢀ 11a
90% ꢀ12a
95% ꢀ 13a
78% ꢀ 14a
O
O
O
O
O
O
C
F
O
OMe O
C
N
N
C
N
C
N
O
O
O
O
O
O
O
O
76% ꢀ 15a
83% ꢀ 16a
76% ꢀ 17a
83% ꢀ 18a
MeO
OHex
O
O
O
N
O
C
O
O
N
C
N
C
O
O
O
O
O
O
70% ꢀ 19a
59% ꢀ 20a
91% ꢀ 21a
N
O
N
O
N
O
O
C
C
N
N
S
O
O
O
O
94% ꢀ 22a
70% ꢀ 23a
aFull experimental details are described in the Supporting Information.
Electronꢀdeficient aryl bromides also worked well providing 4a, 6a, 7a, 8a, 11a, and 17a in 72–90%
yields. In the case of the active esters 17a, 18a, and 19a, high yields were obtained despite the
presence of an orthoꢀsubstituent in the starting material. A Bocꢀprotected amine and a dimethylacetal
protected aldehyde were also found to be compatible with the developed conditions, affording 9a and
10a in yields of 89% and 82%, resp. Heteroaromatic bromides proved reactive under the developed
conditions and 3ꢀbromopyridine was converted into its corresponding NHSꢀester 20a in a good 59%
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isolated yield. 4ꢀBromoisoquinoline and 6ꢀbromoisoquinoline both reacted cleanly affording the
desired NHSꢀesters 21a and 22a in excellent isolated yields of 91% and 94%, resp. Finally, 2ꢀ
bromothiphene was transformed into 23a in a 70% yield.
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Next, our attention was turned towards other active ester derivatives obtained using similar
alkoxycarbonylation reaction conditions. The results of this work are depicted in Scheme 3. The use of
active esters derived from pentafluorophenol is broadly established and has been especially expedient
as an intermediate in the conversion of carboxylic acids into primary amides. This facile conversion
occurs by aminolysis of the active ester with ammonia at room temperature in the course of
minutes.22ꢀ24 When subjected to the developed conditions, the corresponding pentafluorophenyl
benzoates 2b–6b were obtained in isolated yields ranging from 69–99%.
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Hexafluoroisopropyl alcohol was then tested. Active esters obtained using this fluorinated alcohol
serve as practical acylating reagents since the released hexafluoroisopropanol produced upon
conjugation is readily removed by evaporation, thereby simplifying purification. Furthermore, acyl
transfer reactions based on this ester have been shown to occur at low temperatures.25,26 A small
increase in the CO loading from 1.2 to 1.5 equivalents was required in order to obtain satisfactory
conversion using this fluorinated alcohol as the nucleophile, and by doing so, compounds 2c–5c were
obtained in isolated yields as high as 93%.
4ꢀNitrophenol also proved reactive under these slightly modified conditions and two examples, 2d
and 3d, were isolated in excellent 80% and 96%, resp., after column chromatography.27ꢀ29 Finally, Nꢀ
hydroxyphthalimide was applied in the carbonylative coupling to 2ꢀbromoꢀ6ꢀmethoxynaphthalene.
Although, not commonly used as acyl transfer agents, the product constitutes a phthalimideꢀprotected
Oꢀacylhydroxylamine, which may be released by hydrazinolysis.30 Various Oꢀsubstituted
hydroxylamine motifs have found widespread use in the bioconjungation of diverse groups such as
carbohydrates,31 peptides32 and proteins33 among others, and thus, this carbonylative approach towards
Oꢀacylhydroxylamines from aryl halides remains interesting. By applying Nꢀhydroxyphthalimide as
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°
the limiting reagent and at a reaction temperature of 105 C, the corresponding phthalimide protected
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3
aminooxy derivative 2e could be obtained in an 88% isolated yield.
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Scheme 3. Active Ester Formation by Pd-Catalyzed Alkoxycarbonylation of Aryl Bromidesa
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aFull experimental details are described in the Supporting Information.
The alcohols employed in Scheme 3 display marked variation in structural and electronic properties,
and when Nꢀhydroxyphthalimide is disregarded, they are in general considered poor nucleophiles.
An additional advantage of using ex situ generated CO, is the ease of performing 13Cꢀlabeling
experiments by substituting the COꢀprecursor for its 13Cꢀisotopically labeled version.10 By the
application of this technique, both the NHSꢀester of quinolineꢀ2ꢀcarboxylic acid and its 13Cꢀlabeled
counterpart (12C and 13Cꢀ24a) were synthesized starting from 2ꢀbromoquinoline (Scheme 4). Although
the carbonylative coupling of 2ꢀbromoquinoline proved more problematic than for the isoquinoline
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12
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analogs (Scheme 2, compounds 21a and 22a), Cꢀ and Cꢀ24a could be isolated in 51% and 50%
isolated yields, resp., after column chromatography. Subsequent acyl transfer of these building blocks
to nonꢀprotected asparagine, led to unlabeled and 13Cꢀlabeled 25 in good yields, the former of which is
a known synthetic intermediate for the preparation of saquinavir,34 an HIVꢀprotease inhibitor approved
for the treatment of patients suffering HIV infection.16
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Scheme 4. Formal Synthesis of Saquinavir and its 13C-Labeled Analoga
a Full experimental details are described in the supporting information.
In conclusion, general conditions have been reported for the Pdꢀcatalyzed alkoxycarbonylation of
aromatic and heteroaromatic bromides with sterically and electronically demanding alcohols,
affording active esters such as the classical NHSꢀesters. These transformations can be carried out with
near stoichiometric amounts of both the alcohol and CO under mild conditions employing palladium
catalysis allowing a broad substrate scope. Even changes in the alcohol nucleophile afforded the
corresponding activated carboxylic acid derivatives in high yields, proving the generality of the
protocol. We believe that the developed approach will serve as a practical addition or alternative to
already existing methods when designing the synthesis of acylating reagents. Finally, because of the
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simple setup and the use of stoichiometric CO, the methodology is adaptable to Cꢀlabeling, which
13
was applied for preparing a Cꢀisotopeꢀlabeled synthetic intermediate of the HIV protease inhibitor,
saquinavir.
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EXPERIMENTAL SECTION
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General Methods. All purchased chemicals were used as received without further purification. Solvents were
dried according to standard procedures. Flash chromatography was carried out on silica gel 60 (230ꢀ400 mesh).
The chemical shifts are reported in ppm relative to solvent residual peak. The 1H NMR spectra were recorded at
400 MHz, 13C NMR spectra were recorded at 100 MHz and, 19F NMR spectra were recorded at 376 MHz.
Chemical shifts are reported in ppm downfield to TMS (∂ = 0) using the following peak pattern abbreviations:
br, broad; s, singlet; d, doublet; t, triplet; q, quartet; pent, pentet; sext, sextet; sept, septet; m, multiplet; dd,
doublet of doublets; dt, doublet of triplets; ddd, doublet of doublet of doublets; ddt, doublet of doublet of
triplets, and td, triplet of doublets. HRMS was recorded on an LC TOF (ES).
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General Method: Carbonylative Coupling of Aryl Halides with N-Hydroxysuccinimide (NHS). Chamber
A: Pd(dba)2 (8.6 mg, 0.015 mmol), HBF4PtBu3 (4.3 mg, 0.015 mmol), 9ꢀmethylꢀ9Hꢀfluoreneꢀ9ꢀcarbonyl
chloride (145.6 mg, 0.60 mmol), dioxane (3 mL) and and Cy2NMe (257 µL, 1.2 mmol) were added in that order
to chamber A of the twoꢀchamber system, in a glovebox under Argon atmosphere. The chamber was sealed
tightly with a screwcap fitted with a Teflon® seal. Chamber B: Aryl halide (0.50 mmol), Nꢀ
hydroxysuccinimide (NHS) (0.53 mmol), [{Pd(cinnamyl)Cl}2] (7.8 mg, 0.015 mmol), HBF4PtBu3 (8.7 mg, 0.03
mmol), toluene (3 mL) and Cy2NMe (160 µL, 0.75 mmol) were added in that order, to chamber B of the twoꢀ
chamber system (20 mL total volume), in a glovebox under Argon atmosphere. The chamber was sealed tightly
with a screwcap fitted with a Teflon®ꢀseal. The twoꢀchamber system was removed from the glovebox and
placed in a preheated heatblock and was left for 16 h with vigorous stirring at 95 oC. The crude reaction mixture
was then removed from the heat and a small aliquot (40 µL) was removed for 1H NMR analysis using CDCl3 as
solvent. The remaining crude reaction mixture was concentrated in vacuo and purified by flash column
chromatography to afford the desired products.
2,5-Dioxopyrrolidin-1-yl 4-methoxybenzoate (2a). The product was obtained according to general procedure,
1
as a white solid. Eluent 20% acetone in pentane (109.5 mg, 88%); mp 140ꢀ141 °C. H NMR (400 MHz,
13
CDCl3): δ (ppm) 8.08 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 3.88 (s, 3H), 2.89 (s, 4H). C NMR (100
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MHz, CDCl3): δ (ppm) 169.8, 165.3, 161.8, 133.2, 117.4, 114.5, 55.9, 26.0. HRMS (ESIꢀTOF) m/z: [M + Na]+
Calcd for C12H11NO5Na 272.0529; Found 272.0531.
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2,5-Dioxopyrrolidin-1-yl benzoate (3a). The product was obtained according to general procedure, as a white
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solid. Eluent 20% acetone in pentane (96.6 mg, 88%); mp 137ꢀ138 °C. H NMR (400 MHz, CDCl3): δ (ppm)
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8.14 (d, J = 8.0 Hz, 2H), 7.68 (t, J = 8.0 Hz, 1H), 7.53 (t, J = 8.0 Hz, 2H), 2.91 (s, 4H). C NMR (100 MHz,
CDCl3): δ (ppm) 169.6, 162.2, 135.3, 130.9, 129.2, 125.5, 26.0. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C11H9NO4Na 242.0424; Found 242.0427.
2,5-Dioxopyrrolidin-1-yl 4-fluorobenzoate (4a). The product was obtained according to general procedure, as
1
a white solid. Eluent 20% acetone in pentane (94.8 mg, 80%); mp 112ꢀ113 °C. H NMR (400 MHz, CDCl3): δ
(ppm) 8.19ꢀ8.15 (m, 2H), 7.20 (m, 2H), 2.91 (s, 4H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.1, 166.9 (d, JCꢀ
= 256.0 Hz), 160.9, 133.4 (d, JCꢀF = 10.0 Hz), 121.4 (d, JCꢀF = 3.0 Hz), 116.3 (d, JCꢀF = 22.0 Hz), 25.7. 19F
F
NMR (400 MHz, CDCl3): δ (ppm) ꢀ101.3. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C11H8FNO4Na
260.0330; Found 260,0313.
2,5-Dioxopyrrolidin-1-yl 4-butylbenzoate (5a). The product was obtained according to general procedure, as
1
a white solid. Eluent 20% acetone in pentane (103.3 mg, 75%); mp 65ꢀ66 °C. H NMR (400 MHz, CDCl3): δ
(ppm) 8.03 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 2.68 (s, 4H), 2.89 (t, J = 8.0 Hz, 2H), 1.63ꢀ1.59 (m,
2H), 1.35 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.7, 162.2, 151.3, 130.9,
129.3, 122.7, 36.2, 33.4, 25.9, 22.5, 14.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H17NO4Na 298.1050;
Found 298,1052.
2,5-Dioxopyrrolidin-1-yl 4-cyanobenzoate (6a). The product was obtained according to general procedure, as
1
a white solid. Eluent 20% acetone in pentane (87.9 mg, 72%); mp 239ꢀ240 °C. H NMR (400 MHz, CDCl3): δ
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(ppm) 8.24 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 2.93 (s, 4H). C NMR (100 MHz, CDCl3): δ (ppm)
169.1, 160.9, 132.9, 131.3, 129.4, 118.7, 117.7, 26.0. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C12H8N2O4Na 267.0376; Found 267.0371.
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2,5-Dioxopyrrolidin-1-yl biphenyl-4-carboxylate (7a). The product was obtained according to general
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procedure, as a white solid. Eluent 20% acetone in pentane (123.7 mg, 84%); mp 208ꢀ209 °C. H NMR (400
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MHz, CDCl3): δ (ppm) 8.23 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 7.2 Hz, 2H), 7.51ꢀ7.41
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(m, 3H), 2.94 (s, 4H). C NMR (100 MHz, CDCl3): δ (ppm) 169.6, 162.1, 148.0, 139.8, 131.5, 129.4, 128.9,
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127.8, 127.7, 124.1, 26.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C17H13NO4Na 318.0737; Found
318.0739.
2,5-Dioxopyrrolidin-1-yl 4-acetylbenzoate (8a). The product was obtained according to general procedure, as
a white solid. Eluent 20% acetone in pentane (101.3 mg, 78%); mp 114ꢀ115 °C. 1H NMR (400 MHz, CDCl3): δ
(ppm) 8.22 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 2.92 (s, 4H), 2.65 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ (ppm) 197.4, 169.3, 161.5, 141.9, 131.2, 129.1, 128.8, 27.2, 26.0. HRMS (ESIꢀTOF) m/z: [M + Na]+
Calcd for C13H11NO5Na 284.0529; Found 284.0539.
2,5-Dioxopyrrolidin-1-yl 4-(tert-butoxycarbonylamino)benzoate (9a). The product was obtained according
1
to general procedure, as a white solid. Eluent 20% acetone in pentane (148.7 mg, 89%); mp 177ꢀ178 °C. H
NMR (400 MHz, CDCl3): δ (ppm) 8.05 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 6.76 (br s, 1H), 2.90 (s,
4H), 1.54 (s, 9H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.7, 161.7, 152.2, 144.9, 132.5, 119.1, 117.8, 81.9,
28.6, 26.0. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H18N2O6Na 357.1057; Found 357.1064.
2,5-Dioxopyrrolidin-1-yl 4-(dimethoxymethyl)benzoate (10a). The product was obtained according to
general procedure, as a white solid. Eluent 20% acetone in pentane (120.5 mg, 82%); mp 108ꢀ109 °C. 1H NMR
(400 MHz, CDCl3): δ (ppm) 8.14 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H),5.48 (s, 1H), 3.32 (s, 6H), 2.91
(s, 4H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.5, 161.9, 145.5, 130.9, 127.7, 125.4, 102.2, 52.9, 26.0.
HRMS (ESIꢀTOF) m/z: [M + K]+ Calcd for C14H15NO6K 332.0531; Found 332.0552.
2,5-Dioxopyrrolidin-1-yl 3-(trifluoromethyl)benzoate (11a). The product was obtained according to general
1
procedure, as a white solid. Eluent 20% acetone in pentane (130.5 mg, 90%); mp 96ꢀ97 °C. H NMR (400
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MHz, CDCl3): δ (ppm) 8.40 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.69 (dd, J = 8.0, 8.0
Hz, 1H), 2.93 (s, 4H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.2, 161.1, 134.0, 132.2 (q, JCꢀF = 33.0 Hz),
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131.7 (q, JCꢀF = 3.0 Hz), 130.0, 127.8 (q, JCꢀF = 4.0 Hz), 126.5, 123.6 (q, JCꢀF = 271.0 Hz), 26.0. F NMR (400
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MHz, CDCl3): δ (ppm) ꢀ62.9. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C12H8F3NO4Na 310.0298; Found
310.0298.
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2,5-Dioxopyrrolidin-1-yl 3,4-dimethylbenzoate (12a). The product was obtained according to general
1
procedure, as a white solid. Eluent 20% acetone in pentane (111.1 mg, 90%); mp 157ꢀ158 °C. H NMR (400
MHz, CDCl3): δ (ppm) 7.90 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 2.90 (s, 4H), 2.35 (s,
3H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.8, 161.9, 155.0, 149.3.2, 125.7, 117.4, 112.8,
110.9, 56.5, 56.4, 25.9. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C13H13NO4Na 270.0737; Found 270.0735.
2,5-Dioxopyrrolidin-1-yl 3,4-dimethoxybenzoate (13a). The product was obtained according to general
1
procedure, as a white solid. Eluent 20% acetone in pentane (133.2 mg, 95%); mp 178ꢀ179 °C. H NMR (400
MHz, CDCl3): δ (ppm) 7.82 (dd, J = 8.4, 1.2 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 6.93 (d, 8.4 Hz, 1H), 3.96 (s,
3H), 3.93 (s, 3H), 2.90 (s, 4H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.8, 161.9, 155.0, 149.3.2, 125.7,
117.4, 112.8, 110.9, 56.5, 56.4, 25.9. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C13H13NO6Na 302.0635;
Found 302.0637.
2,5-Dioxopyrrolidin-1-yl 2-naphthoate (14a). The product was obtained according to general procedure, as a
white solid. Eluent 20% acetone in pentane (104.7 mg, 78%); mp 164ꢀ165 °C. 1H NMR (400 MHz, CDCl3): δ
(ppm) 8.77 (s, 1H), 8.08 (dd, J = 8.8, 2.0 Hz, 1H), 7.99ꢀ7.90 (m, 3H), 7.69ꢀ7.58 (m, 2H), 2.93 (s, 4H). 13C
NMR (100 MHz, CDCl3): δ (ppm) 169.7, 162.4, 136.6, 133.3, 132.6, 129.9, 129.7, 129.2, 128.2, 127.5, 125.4,
122.5, 26.0. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H11NO4Na 292.0580; Found 292.0579.
2,5-Dioxopyrrolidin-1-yl 1-naphthoate (15a). The product was obtained according to general procedure, as a
1
white solid. Eluent 20% acetone in pentane (101.8 mg, 76%); mp 140ꢀ141 °C. H NMR (400 MHz, CDCl3): δ
(ppm) 8.80 (d, J = 8.4 Hz, 1H), 8.45 (dd, J = 7.2, 1.2 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz,
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1H), 7.68ꢀ7.65 (m, 1H), 7.61ꢀ7.55 (m, 2H), 2.95 (s, 4H). C NMR (100 MHz, CDCl3): δ (ppm) 169.7, 162.4,
135.8, 133.9, 132.1, 131.7, 129.0, 128.9, 127.1, 125.5, 124.7, 121.8, 26.0. HRMS (ESIꢀTOF) m/z: [M + Na]+
Calcd for C15H11NO4Na 292.0580; Found 292.0579.
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2,5-Dioxopyrrolidin-1-yl 6-methoxy-2-naphthoate (16a). The product was obtained according to general
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procedure, as a white solid. Eluent 20% acetone in pentane (124.0 mg, 83%); mp 199ꢀ200 °C. H NMR (400
MHz, CDCl3): δ (ppm) 8.66 (s, 1H), 8.04 (dd, J = 8.4, 1.6 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.8
Hz, 1H), 7.23 (dd, J = 9.2, 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 3.96 (s, 3H), 2.93 (s, 4H). 13C NMR (100
MHz, CDCl3): δ (ppm) 169.8, 162.5, 160.8, 138.5, 133.0, 131.6, 128.0, 127.7, 126.3, 120.6, 120.1, 106.2, 55.8,
26.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H13NO5Na 322.0686; Found 322.0687.
2,5-Dioxopyrrolidin-1-yl 2-fluorobenzoate (17a). The product was obtained according to general procedure,
as a white solid. Eluent 20% acetone in pentane (90.5 mg, 76%); mp 109ꢀ110 °C. 1H NMR (400 MHz, CDCl3):
δ (ppm) 8.10ꢀ8.06 (m, 1H), 7.69ꢀ7.64 (m, 1H), 7.31ꢀ7.20 (m, 2H), 2.91 (s, 4H). 13C NMR (100 MHz, CDCl3): δ
(ppm) 169.3, 161.9 (d, JCꢀF = 262.8 Hz), 159.6 (d, JCꢀF = 4.2 Hz), 137.1 (d, JCꢀF = 9.2 Hz), 133.0, 124.8 (d, JCꢀF
= 4.8 Hz), 117.7 (d, JCꢀF = 21.5 Hz), 114.2 (d, JCꢀF = 9.9 Hz), 26.0. 19F NMR (400 MHz, CDCl3): δ (ppm) ꢀ
105.2. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C11H8FNO4Na 260.0330; Found 260.0326.
2,5-Dioxopyrrolidin-1-yl 2-methoxybenzoate (18a). The product was obtained according to general
1
procedure, as a white solid. Eluent 20% acetone in pentane (79.8 mg, 64%); mp 179ꢀ180 °C. H NMR (400
MHz, CDCl3): δ (ppm) 8.05 (dd, J = 8.0 Hz, 1.6, 1H), 7.62ꢀ7.57 (m, 1H), 7.05ꢀ7.01 (m, 2H), 3.92 (s, 3H), 2.88
(s, 4H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.8, 161.0, 160.7, 136.3, 133.1, 120.6, 114.3, 112.5, 56.4,
26.0. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C12H11NO5Na 272.0529; Found 272.0533.
2,5-Dioxopyrrolidin-1-yl 2-(hexyloxy)benzoate (19a). The product was obtained according to general
1
procedure, as a white solid. Eluent 20% acetone in pentane (112.2 mg, 70%); mp 66ꢀ67 °C. H NMR (400
MHz, CDCl3): δ (ppm) 8.02 (dd, J = 8.0, 2.0 Hz, 1H), 7.58ꢀ7.53 (m, 1H), 7.02ꢀ6.98 (m, 2H), 4.05 (t, J = 8.0 Hz,
2H), 2.88 (s, 4H), 1.83 (m, 2H), 1.33ꢀ1.29 (m, 2H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
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(ppm) 169.8, 160.7, 160.6, 136.1, 133.0, 120.4, 114.6, 113.5, 69.4, 31.8, 29.3, 26.0, 25.8, 22.9, 14.3. HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C17H21NO5Na 342.1312; Found 342.1314.
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2,5-Dioxopyrrolidin-1-yl nicotinate (20a). The product was obtained according to general procedure, as a
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white solid. Eluent 20% acetone in pentane (64.4 mg, 59%); mp 137ꢀ138 °C. H NMR (400 MHz, CDCl3): δ
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(ppm) 9.33 (dd, J = 2.0, 0.8 Hz, 1H), 8.90 (dd, J = 4.8, 1.6 Hz, 1H), 8.39 (dt, J = 8.0, 2.0 Hz, 1H), 7.49ꢀ7.46 (m,
1H), 2.92 (s, 4H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.2, 161.1, 155.5, 151.8, 138.1, 123.9, 121.9, 26.0.
Spectral data was in according with those reported in the literature.35
2,5-Dioxopyrrolidin-1-yl isoquinoline-4-carboxylate (21a). The product was obtained according to general
1
procedure, as a white solid. Eluent 20% acetone in pentane (122.3 mg, 91%); mp 172ꢀ173 °C. H NMR (400
MHz, CDCl3): δ (ppm) 9.45 (s, 1H), 9.37 (s, 1H), 8.75 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.88ꢀ7.84
(m, 1H), 7.73ꢀ7.69 (m, 1H), 2.95 (s, 4H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.5, 161.8, 159.0, 148.1,
133.9, 133.5, 128.9, 128.7, 128.6, 124.8, 116.4, 26.0. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C14H10N2O4Na 293.0533; Found 293.0513.
2,5-Dioxopyrrolidin-1-yl isoquinoline-5-carboxylate (22a). The product was obtained according to general
1
procedure, as a white solid. Eluent 20% acetone in pentane (126.9 mg, 94%); mp 202ꢀ203 °C. H NMR (400
MHz, CDCl3): δ (ppm) 9.34 (s, 1H), 8.69ꢀ8.60 (m, 3H), 8.28 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 2.95
(s, 4H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.6, 161.4, 153.5, 146.1, 136.2, 135.6, 134.7, 129.1, 126.4,
120.9, 118.2, 26.0. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C14H11N2O4 271.0713; Found 271.0713.
2,5-Dioxopyrrolidin-1-yl thiophene-2-carboxylate (23a). The product was obtained according to general
1
procedure, as a white solid. Eluent 20% acetone in pentane (78.6 mg, 70%); mp 157ꢀ158 °C. H NMR (400
MHz, CDCl3): δ (ppm) 8.03 (dd, J = 4.0, 1.2 Hz, 1H), 7.78 (dd, J = 4.8, 1.2 Hz, 1H), 7.21ꢀ7.19 (m, 1H), 2.90 (s,
13
4H). C NMR (100 MHz, CDCl3): δ (ppm) 169.4, 157.7, 136.9, 136.0, 128.7, 127.3, 26.0. HRMS (ESIꢀTOF)
m/z: [M + K]+ Calcd for C9H7NO4SK 263.9727; Found 263.9748.
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2,5-Dioxopyrrolidin-1-yl quinoline-2-carboxylate (24a). The product was obtained according to general
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procedure, as a white solid. Eluent 20% acetone in pentane (69.0 mg, 51%); mp 172ꢀ173 °C. H NMR (400
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MHz, CDCl3): δ (ppm) 8.35 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.90 (d, J =
8.0 Hz, 1H), 7.82ꢀ7.80 (m, 1H), 7.71ꢀ7.68 (m, 1H), 2.94 (s, 4H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.2,
161.0, 148.1, 137.9, 131.3, 131.1, 130.1, 129.9, 127.9, 121.9, 26.1. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C14H11N2O4 271.0713; Found 271.0738.
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[13C]-2,5-Dioxopyrrolidin-1-yl quinoline-2-carboxylate (24a). The product was obtained according to
general procedure, as a white solid. Eluent 30% acetone in pentane (67.5 mg, 50%); mp 172ꢀ173 °C. 1H NMR
(400 MHz, CDCl3): δ (ppm) 8.37 (d, J = 8.8 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.22 (dd, J = 8.4, 1.6 Hz, 1H),
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7.92 (d, J = 8.4 Hz, 1H), 7.86ꢀ7.82 (m, 1H), 7.74ꢀ7.70 (m, 1H), 2.95 (s, 4H). C NMR (100 MHz, CDCl3): δ
(ppm) 161.1 (13C enriched ꢀCOOꢀ). HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C14H11N2O4 271.0713; Found
271.0734.
(Quinoline-2-carbonyl)-L-asparagine (12C-25). In a round bottom flask, 2,5ꢀdioxopyrrolidinꢀ1ꢀyl quinolineꢀ2ꢀ
carboxylate (12Cꢀ24a) (150 mg, 0.56 mmol) and LꢀAsparagine (80.9 mg, 0.62 mmol) was dissolved in H2O (7.5
mL), MeOH (11 mL) and acetone (400 µL). To this mixture was added Et3N (188 µL, 1.35 mmol) and the
reaction was stirred at rt. for 12 h after which TLC analysis indicated full conversion of the starting material.
EtOAc (50 mL) was added and pH of the aqueous layer was adjusted to approx. 1 by addition of 2M HCl. The
organic phase was separated, and the aqueous layer was extracted with further 3 portions of EtOAc (70 mL)
and 2 portions of DCM (70 mL). The combined organic phases were then washed with brine, dried with
NaSO4, filtered and concentrated in vacuo to leave a solid residue. The solids were washed with cold CH2Cl2
(3x2 mL) to leave a white solid which were collected and dried to leave the product compound as a colorless
powder (140 mg, 87%); mp 198ꢀ199 °C. 1H NMR (400 MHz, DMSOꢀd6): δ (ppm) 12.85 (br s, 1H), 9.18 (d, J=
8.0 Hz, 1H), 8.60 (d, J= 8.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.0 Hz,
1H), 7.89 (ddd, J = 8.4 Hz, 6.8 Hz, 1.6 Hz, 1H), 7.74 (ddd, J = 8.0 Hz, 6.8 Hz, 0.08 Hz, 1H), 7.52 (br s, 1H),
7.01 (br s, 1H), 4.83 (dt, J = 8.6, 5.3 Hz, 1H), 2.87 (dd, J = 16 Hz, 6 Hz, 1H), 2.74 (dd, J = 16 Hz, 4.8 Hz, 1H).
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The Journal of Organic Chemistry
13C NMR (100 MHz, DMSOꢀd6): δ (ppm) 173.0, 172.3, 163.9, 149.9, 146.4, 138.6, 131.1, 129.7, 129.4, 128.7,
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128.6, 119.0, 49.3, 36.8. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C14H14N3O4 288.0979; Found 288.0979.
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(Quinoline-2-carbonyl)-L-asparagine (13C-25). In a round bottom flask, 2,5ꢀdioxopyrrolidinꢀ1ꢀyl quinolineꢀ2ꢀ
carboxylate (13Cꢀ24a) (44 mg, 0.16 mmol), LꢀAsparagine (23.7 mg, 0.18 mmol) was dissolved in H2O (2.2
mL), MeOH (3.3 mL) and acetone (100 µL). To this mixture was added Et3N (55 µL, 0.39 mmol) and the
reaction was stirred at rt. for 12 h after which TLC analysis indicated full conversion of the starting material.
EtOAc (20 mL) was added and pH of the aqueous layer was adjusted to approx. 1 by addition of 2M HCl. The
organic phase was separated, and the aqueous layer was extracted w. further 3 portions of EtOAc (20 mL) and 2
portions of DCM (20 mL). The combined organic phases were then washed with brine, dried with NaSO4,
filtered and concentrated in vacuo to leave a solid residue. The solids were washed with cold CH2Cl2 (3x1 mL)
to leave a white solid which were collected and dried to leave the product compound as a colorless powder (34
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mg, 74%); mp 198ꢀ199 °C. H NMR (400 MHz, CDCl3): δ (ppm) 12.85 (br s, 1H), 9.18 (d, J= 8.0 Hz, 1H),
8.60 (d, J= 8.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.89 (ddd, J
= 8.4 Hz, 6.8 Hz, 1.6 Hz, 1H), 7.74 (ddd, J = 8.0 Hz, 6.8 Hz, 0.08 Hz, 1H), 7.52 (br s, 1H), 7.01 (br s, 1H),
4.83 (m, 1H), 2.87 (dd, J = 16 Hz, 6 Hz, 1H), 2.74 (dd, J = 16 Hz, 4.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
(ppm) 163.4 (s, 13Cꢀenriched). HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C14H14N3O4 289.1012; Found
289.1015.
General Method for Carbonylative Coupling of Aryl Halides with Pentafluorophenol. Chamber A:
Pd(dba)2 (8.6 mg, 0.015 mmol), HBF4PtBu3 (4.3 mg, 0.015 mmol), 9ꢀmethylꢀ9Hꢀfluoreneꢀ9ꢀcarbonyl chloride
(145.6 mg, 0.60 mmol), dioxane (3 mL) and and Cy2NMe (257 µL, 1.2 mmol) were added in that order to
chamber A of the twoꢀchamber system, in a glovebox under Argon atmosphere. The chamber was sealed
tightly with a screwcap fitted with a Teflon®ꢀseal. Chamber B: Aryl halide (0.50 mmol), Pentafluorophenol
(0.53 mmol), [{Pd(cinnamyl)Cl}2] (7.8 mg, 0.015 mmol), HBF4PtBu3 (8.7 mg, 0.03 mmol), toluene (3 mL) and
Cy2NMe (160 µL, 0.75 mmol) were added in that order, to chamber B of the twoꢀchamber system (20 mL total
volume), in a glovebox under Argon atmosphere. The chamber was sealed tightly with a screwcap fitted with a
Teflon®ꢀseal. The twoꢀchamber system was removed from the glovebox and placed in a preheated heatblock
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o
and was left for 16 h with vigorous stirring at 95 C. The crude reaction mixture was then removed from the
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heat and a small aliquot (40 µL) was removed for H NMR analysis using CDCl3 as solvent. The remaining
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crude reaction mixture was concentrated in vacuo and purified by flash column chromatography to afford the
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desired products.
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Perfluorophenyl 6-methoxy-2-naphthoate (2b). The product was obtained according to general procedure, as
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a white solid. Eluent 20% dichloromethane in pentane (179.8 mg, 98%); mp 98ꢀ99 °C. H NMR (400 MHz,
CDCl3): δ (ppm) 8.72 (s, 1H), 8.12 (dd, J = 8.4, 1.6 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H),
7.25 (dd, J = 8.8, 2.4 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 3.98 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm)
163.2, 160.8, 138.5, 133.1, 131.6, 128.2, 127.8, 126.5, 122.0, 120.6, 106.2, 55.8. 19F NMR (400 MHz, CDCl3):
δ (ppm) ꢀ152.39 to ꢀ152.49 (m, 2F), ꢀ158.21 (t, J = 23.2 Hz, 1F), ꢀ162.38 to ꢀ162.53 (m, 2F). HRMS (ESIꢀTOF)
m/z: [M + H]+ Calcd for C18H10F5O3 369.0545; Found 369.0534.
Perfluorophenyl 4-cyanobenzoate (3b). The product was obtained according to general procedure, as a white
solid. Eluent 30% dichloromethane in pentane (122.7 mg, 78%); mp 115ꢀ116 °C. 1H NMR (400 MHz, CDCl3):
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δ (ppm) 8.32 (dd, J = 8.4, 1.6 Hz, 2H), 7.86 (dd, J = 8.4, 2.0 Hz, 2H). C NMR (100 MHz, CDCl3): δ (ppm)
161.5, 133.0, 131.5, 131.1, 118.5, 117.8. 19F NMR (400 MHz, CDCl3): δ (ppm) ꢀ152.23 to ꢀ152.32 (m, 2F), ꢀ
156.77 (t, J = 23.2 Hz, 1F), ꢀ161.53 to ꢀ161.69 (m, 2F). HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C14H5F5NO2 314.0235; Found 314.0249.
Perfluorophenyl 4-fluorobenzoate (4b). The product was obtained according to general procedure, as a white
solid. Eluent 10% dichloromethane in pentane (108.7 mg, 71%); mp 61ꢀ62 °C. 1H NMR (400 MHz, CDCl3): δ
(ppm) 8.25ꢀ8.22 (m, 2H), 7.26ꢀ7.20 (m, 2H). 13C NMR (100 MHz, CDCl3): δ (ppm) 167.2 (d, JCꢀF = 255.8 Hz),
161.9, 133.9 (d, JCꢀF = 9.7 Hz, 2C), 123.5 (d, JCꢀF = 6.0 Hz), 116.6 (d, JCꢀF = 22.1 Hz, 2C), 25.7. 19F NMR (400
MHz, CDCl3): δ (ppm) ꢀ101.92 (s,1F), ꢀ152.46 to ꢀ152.56 (m, 2F), ꢀ157.73 (t, J = 22.8 Hz, 1F), ꢀ162.13 to ꢀ
162.28 (m, 2F). HRMS (ESIꢀTOF) m/z: [M + K]+ Calcd for C13H4F6O2K 344.9753; Found 344.9743.
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The Journal of Organic Chemistry
Perfluorophenyl isoquinoline-5-carboxylate (5b). The product was obtained according to general procedure,
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as a white solid. Eluent 30% dichloromethane in pentane (168.1 mg, 99%); mp 142ꢀ143 °C. H NMR (400
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MHz, CDCl3): δ (ppm) 9.38 (dd, J = 5.2, 1.2 Hz, 1H), 8.78ꢀ8.72 (m, 3H), 8.33 (d, J = 8.4 Hz, 1H), 7.77 (t, J =
7.6 Hz, 1H) . 13C NMR (100 MHz, CDCl3): δ (ppm) 161.7, 153.3, 145.9, 136.4, 135.4, 134.7, 128.9, 126.2,
122.1, 117.9. 19F NMR (400 MHz, CDCl3): δ (ppm) ꢀ152.30 to ꢀ152.39 (m, 2F), ꢀ157.34 (t, J = 22.8 Hz, 1F), ꢀ
161.86 to ꢀ162.01 (m, 2F). HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H7F5NO2 340.0391; Found
340.0387.
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Perfluorophenyl thiophene-2-carboxylate (6b). The product was obtained according to general procedure, as
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a white solid. Eluent 30% dichloromethane in pentane (102.1 mg, 69%); mp 46ꢀ47 °C. H NMR (400 MHz,
CDCl3): δ (ppm) 8.06 (dd, J = 5.2, 1.2 Hz, 1H), 7.78 (dd, J = 6.0, 1.2 Hz, 1H), 7.24ꢀ7.22 (m, 1H). 13C NMR
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(100 MHz, CDCl3): δ (ppm) 158.2, 136.8, 135.7, 129.9, 128.8. F NMR (400 MHz, CDCl3): δ (ppm) ꢀ152.20
to ꢀ152.39 (m, 2F), ꢀ157.67 (t, J = 22.8 Hz, 1F), ꢀ162.16 to ꢀ162.31 (m, 2F). HRMS could not be obtained for
compound 6b, possibly due to rapid hydrolysis in solution. However, when 6b (2 mg) was stirred with KOH (5
mg) at rt. in MeCN/H2O (1:1) until full consumption of the starting ester was observed as indicated by TLCꢀ
analysis, the presence of the corresponding 2ꢀthiophenecarboxylic acid and perfluorophenol was confirmed by
HRMS. Thiophene-2-carboxylic acid: HRMS (ESIꢀTOF) m/z: [M]ꢀ Calcd for C5H3O2S 126.9859; Found
126.9857. Perfluorophenol: HRMS (ESIꢀTOF) m/z: [M]ꢀ Calcd for C6F5O 182.9875; Found 182.9880.
General Method for Carbonylative Coupling of Aryl Halides with Hexafluoroisopropanol. Chamber A:
Pd(dba)2 (10.8 mg, 0.019 mmol), HBF4PtBu3 (4.3 mg, 0.015 mmol), 9ꢀmethylꢀ9Hꢀfluoreneꢀ9ꢀcarbonyl chloride
(182.0 mg, 0.75 mmol), dioxane (3 mL) and and Cy2NMe (321 µL, 1.5 mmol) were added in that order to
chamber A of the twoꢀchamber system, in a glovebox under Argon atmosphere. The chamber was sealed
tightly with a screwcap fitted with a Teflon®ꢀseal. Chamber B: Aryl halide (0.50 mmol),
Hexafluoroisopropanol (1.25 mmol), [{Pd(cinnamyl)Cl}2] (7.8 mg, 0.015 mmol), HBF4PtBu3 (8.7 mg, 0.03
mmol), toluene (3 ml) and Cy2NMe (160 µL, 0.75 mmol) were added in that order, to chamber B of the twoꢀ
chamber system (20 mL total volume), in a glovebox under Argon atmosphere. The chamber was sealed tightly
with a screwcap fitted with a Teflon®ꢀseal. The twoꢀchamber system was removed from the glovebox and
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placed in a preheated heatblock and was left for 16 h with vigorous stirring at 95 oC. The crude reaction mixture
was then removed from the heat and a small aliquot (40 µL) was removed for 1H NMR analysis using CDCl3 as
solvent. The remaining crude reaction mixture was concentrated in vacuo and purified by flash column
chromatography to afford the desired products.
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1,1,1,3,3,3-Hexafluoropropan-2-yl 6-methoxy-2-naphthoate (2c). The product was obtained according to the
general procedure, as a white solid. Eluent 30% dichloromethane in pentane (147.2 mg, 84%); mp 64ꢀ65 °C .
1H NMR (400 MHz, CDCl3): δ (ppm) 8.61 (d, J = 1.2 Hz, 1H), 8.05 (dd, J = 8.0, 1.6 Hz, 1H), 7.89 (d, J = 8.8
Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.24 (dd, J = 8.8, 2.4 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6.10 (m, 1H), (3.98
(s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 163.9, 160.8, 138.5, 132.8, 131.6, 128.1, 127.7, 126.2, 121.9,
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121.0 (q, J = 283.3 Hz, 2C), 120.6, 106.1, 67.2 (spt, , J = 34.4 Hz, 1C), 55.8. F NMR (400 MHz, CDCl3): δ
(ppm) ꢀ73.12 (d, J = 6.4 Hz). HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C15H11F6O3 353.0607; Found
353.0598.
1,1,1,3,3,3-Hexafluoropropan-2-yl 4-(dimethoxymethyl)benzoate (3c). The product was obtained according
to the general procedure, as a white solid. Eluent 30% dichloromethane in pentane (147.9 mg, 83%); mp 51ꢀ52
°C. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.12 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 6.02 (spt, J = 6.0
13
Hz, 1H), 3.34 (s, 6H). C NMR (100 MHz, CDCl3): δ (ppm) 163.4, 145.5, 130.8, 127.7, 127.2, 120.9 (q, J =
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283.2 Hz, 2C), 102.3, 67.3 (spt, , J = 34.6 Hz, 1C), 52.9. F NMR (400 MHz, CDCl3): δ (ppm) ꢀ73.24 (d, J =
4.8 Hz). HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C13H13F6O4 347.0713; Found 347.0741.
1,1,1,3,3,3-Hexafluoropropan-2-yl 4-(tert-butoxycarbonylamino)benzoate (4c). The product was obtained
according to the general procedure, as a white solid. Eluent 30% dichloromethane in pentane (156.8 mg, 81%);
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mp 62ꢀ63 °C. H NMR (400 MHz, CDCl3): δ (ppm) 8.04 (dd, J = 6.8, 2.0 Hz, 2H), 7.50 (dd, J = 7.2, 2.0 Hz,
2H), 6.77 (br s, 1H), 5.99 (spt, J = 6.4 Hz, 1H), 1.54 (s, 9H). 13C NMR (100 MHz, CDCl3): δ (ppm) 163.1,
152.3, 144.8, 132.3, 121.0, 120.9 (q, J = 280.5 Hz, 2C), 117.9, 82.0, 67.1 (spt, J = 34.4 Hz, 1C), 28.6. 19F
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The Journal of Organic Chemistry
NMR (400 MHz, CDCl3): δ (ppm) ꢀ73.21. HRMS (ESIꢀTOF) m/z: [M + K]+ Calcd for C15H15F6NO4K
426.0537; Found 426.0516.
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1,1,1,3,3,3-Hexafluoropropan-2-yl isoquinoline-7-carboxylate (5c). The product was obtained according to
the general procedure, as a white solid. Eluent 1% methanol in dichloromethane (150.6 mg, 93%); mp 118ꢀ119
°C. 1H NMR (400 MHz, CDCl3): δ (ppm) 9.36 (s, 1H), 8.76ꢀ8.72 (m, 2H), 8.60 (dd, J = 7.6, 1.2 Hz, 1H), 8.30
(d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 6.13 (spt, J = 6.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ (ppm)
162.6, 153.7, 146.3, 136.4, 135.8, 134.9, 129.2, 126.5, 122.3, 120.9 (q, J = 280.5 Hz, 2C), 118.2, 67.2 (spt, J =
34.6 Hz, 1C). 19F NMR (400 MHz, CDCl3): δ (ppm) ꢀ72.99. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C13H8F6NO2 324.0454; Found 324.0451.
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General Method for Carbonylative Coupling of Aryl Halides with p-Nitrophenol. Chamber A: Pd(dba)2
(10.8 mg, 0.019 mmol), HBF4PtBu3 (5.4 mg, 0.015 mmol), 9ꢀmethylꢀ9Hꢀfluoreneꢀ9ꢀcarbonyl chloride (182.0
mg, 0.75 mmol), dioxane (3 mL) and and Cy2NMe (321 µL, 1.5 mmol) were added in that order to chamber A
of the twoꢀchamber system, in a glovebox under Argon atmosphere. The chamber was sealed tightly with a
screwcap fitted with a Teflon®ꢀseal. Chamber B: Aryl halide (0.50 mmol), pꢀnitrophenol (0.75 mmol),
[{Pd(cinnamyl)Cl}2] (7.8 mg, 0.015 mmol), HBF4PtBu3 (8.7 mg, 0.03 mmol), toluene (3 mL) and Cy2NMe
(160 µL, 0.75 mmol) were added in that order, to chamber B of the twoꢀchamber system (20 mL total volume),
in a glovebox under Argon atmosphere. The chamber was sealed tightly with a screwcap fitted with a Teflon®ꢀ
seal. The twoꢀchamber system was removed from the glovebox and placed in a preheated heatblock and was
o
left for 16 h with vigorous stirring at 95 C. The crude reaction mixture was then removed from the heat and a
small aliquot (40 µL) was removed for 1H NMR analysis using CDCl3 as solvent. The remaining crude reaction
mixture was concentrated in vacuo and purified by flash column chromatography to afford the desired products.
4-Nitrophenyl 6-methoxy-2-naphthoate (2d).The product was obtained according to general procedure, as a
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white solid. Eluent 30% dichloromethane in pentane (128.9 mg, 80%); mp 161ꢀ162 °C. H NMR (400 MHz,
CDCl3): δ (ppm) 8.70 (s, 1H), 8.34 (dd, J = 7.2, 2.4 Hz, 2H), 8.13 (dd, J = 8.8, 2.0 Hz, 1H), 7.90 (d, J = 8.8 Hz,
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1H), 7.84 (d, J = 8.8, 1H), 7.46 (dd, J = 6.8, 2.0 Hz, 2H), 7.25 (dd, J = 8.8, 2.4 Hz, 1H), 7.20 (d, J = 2.4 Hz,
1H), 3.98 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 164.9, 160.6, 156.3, 145.7, 138.2, 132.5, 131.5, 128.2,
127.7, 126.4, 125.6, 123.7, 123.0, 120.5, 106.2, 55.8. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C18H14NO5
324.0866; Found 324.0884.
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4-Nitrophenyl 4-(tert-butoxycarbonylamino)benzoate (3d). The product was obtained according to the
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general procedure, as a white solid. Eluent dichloromethane (132.0 mg, 96%); mp 185ꢀ186 °C. H NMR (400
MHz, CDCl3): δ (ppm) 8.31 (dd, J = 7.2, 2.4 Hz, 2H), 8.12 (dd, J = 6.8, 1.6 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H),
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7.41 (dd, J = 6.8, 2.0 Hz, 2H), 6.78 (b, 1H), 1.54 (s, 9H). C NMR (100 MHz, CDCl3): δ (ppm) 164.1, 156.2,
152.4, 145.6, 144.3, 132.1, 125.6, 123.0, 122.8, 117.9, 81.9, 28.6. HRMS (ESIꢀTOF) m/z: [M + K]+ Calcd for
C18H18N2O6K 397.1057; Found 397.1059.
General Method for Carbonylative Coupling of Aryl Halides with N-Hydroxyphthalimide. Chamber A:
Pd(dba)2 (10.8 mg, 0.019 mmol), HBF4PtBu3 (5.4 mg, 0.015 mmol), 9ꢀmethylꢀ9Hꢀfluoreneꢀ9ꢀcarbonyl chloride
(182.0 mg, 0.75 mmol), dioxane (3 mL) and and Cy2NMe (321 µL, 1.5 mmol) were added in that order to
chamber A of the twoꢀchamber system, in a glovebox under Argon atmosphere. The chamber was sealed
tightly with a screwcap fitted with a Teflon®ꢀseal. Chamber B: Aryl halide (1.0 mmol), Nꢀhydroxyphthalimide
(0.5 mmol), [{Pd(cinnamyl)Cl}2] (7.8 mg, 0.015 mmol), HBF4PtBu3 (8.7 mg, 0.03 mmol), toluene (3 mL) and
Cy2NMe (160 µL, 0.75 mmol) were added in that order, to chamber B of the twoꢀchamber system (20 mL total
volume), in a glovebox under Argon atmosphere. The chamber was sealed tightly with a screwcap fitted with a
Teflon®ꢀseal. The twoꢀchamber system was removed from the glovebox and placed in a preheated heatblock
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and was left for 16 h with vigorous stirring at 95 C. The crude reaction mixture was then removed from the
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heat and a small aliquot (40 µL) was removed for H NMR analysis using CDCl3 as solvent. The remaining
crude reaction mixture was concentrated in vacuo and purified by flash column chromatography to afford the
desired products.
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The Journal of Organic Chemistry
1,3-Dioxoisoindolin-2-yl 6-methoxy-2-naphthoate (2e). The product was obtained according to the general
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procedure, as a white solid. Eluent 20% ethyl acetate in pentane (152.0 mg, 88%); mp 178ꢀ179 °C. H NMR
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(400 MHz, CDCl3): δ (ppm) 8.72 (s, 1H), 8.09 (dd, J = 8.4, 1.6 Hz, 1H), 7.95ꢀ7.93 (m, 2H), 7.88 (d, J = 9.2 Hz,
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1H), 7.84ꢀ7.81 (m, 3H), 7.24 (dd, J = 8.8, 2.4 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 3.97 (s, 3H). C NMR (100
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MHz, CDCl3): δ (ppm) 163.4, 162.6, 160.8, 138.5, 135.1, 133.0, 131.6, 129.4, 128.0, 127.7, 126.3, 124.3,
120.6, 120.3, 106.2, 55.8. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C20H14NO5 348.0866; Found 348.0849.
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ASSOCIATED CONTENT
Supporting Information
1
General methods, description of COware and the HꢀCap system, copies of H NMR and 13C NMR spectrums for all
compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* lindhardt@eng.au.dk, ts@chem.au.dk
ACKNOWLEDGMENT
We are deeply appreciative of generous financial support from the Danish National Research Foundation, (grant no.
DNRF59), the Villum Foundation, the Danish Council for Independent Research: Technology and Production Sciences, the
Lundbeck Foundation, the Carlsberg Foundation, and Aarhus University for financial support of this work. Furthermore,
we thank the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for a grant to Angelina Maria de
Almeida (no. BEX 6280/13ꢀ7) and FAPEMIG.
REFERENCES
(1)
(2)
Nicolaou, K. C.; Chakraborty, T. K.; Piscopio, A. D.; Minowa, N.; Bertinato, P. J. Am. Chem. Soc. 1993,
115, 4419.
Marino, J. P.; McClure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucci, F. C. J. Am. Chem. Soc. 2002, 124,
1664.
(3)
(4)
(5)
(6)
(7)
Ghosh, A. K.; Wang, Y.; Kim, J. T. J. Org. Chem. 2001, 66, 8973.
Mulzer, J.; Mantoulidis, A.; Ohler, E. J. Org. Chem. 2000, 65, 7456.
Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827.
Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
Kluger, R.; Alagic, A. Bioorg. Chem. 2004, 32, 451.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 25
(8)
Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067.
1
2
3
4
5
6
7
8
(9)
ElꢀFaham, A.; Albericio, F. Chem. Rev. 2011, 111, 6557.
(10)
(11)
(12)
(13)
(14)
(15)
Gawne, G.; Kenner, G. W.; Sheppard, R. C. J. Am. Chem. Soc. 1969, 91, 5669.
Yoo, W. J.; Li, C. J. J. Am. Chem. Soc. 2006, 128, 13064.
EkoueꢀKovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429.
Tan, B.; Toda, N.; Barbas, C. F. Angew Chem Int Edit 2012, 51, 12538.
Lou, R. L.; VanAlstine, M.; Sun, X. F.; Wentland, M. P. Tetrahedron Lett. 2003, 44, 2477.
9
For recent reviews on the progress in carbonylation chemistry see; a) Wu, X. F.; Neumann, H.; Beller, M. Chem. Rev.
2013, 113, 1. b) Gabriele, B.; Mancuso, R.; Salerno, G. Eur. J. Org. Chem. 2012, 35, 6825. c) Wu, X. F.; Neumann, H.;
Beller, M. ChemSusChem 2013, 6, 229. d) Wu, X. F.; Beller, M. ChemCatChem 2012, 4, 447.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
e) Duffy, E. M.; Bhattacharjee, A.; O´Dowd, H.; Devivo, M.; Kanyo, Z.; Martinow, J. G.; Paik, IꢀH.; Sinishtaj, S.;
Wimberly, B.; Wu, Y. Antimicrobial compounds and methods of making and using the same. US Patent 0220566 A1,
August 30, 2012.
(16)
(17)
Wu, X. F.; Neumann, H.; Beller, M. Chem-Eur J 2012, 18, 3831.
Hermange, P.; Lindhardt, A. T.; Taaning, R. H.; Bjerglund, K.; Lupp, D.; Skrydstrup, T. J. Am. Chem. Soc.
2011, 133, 6061.
(18)
9ꢀMethylꢀfluoreneꢀ9ꢀcarbonyl chloride (COgen) and the twoꢀchamber glassware (COware) are commercially
available.
(19)
(20)
(21)
(22)
(23)
Kong, K. C.; Cheng, C. H. J. Am. Chem. Soc. 1991, 113, 6313.
Segelstein, B. E.; Butler, T. W.; Chenard, B. L. J. Org. Chem. 1995, 60, 12.
Okeefe, D. F.; Dannock, M. C.; Marcuccio, S. M. Tetrahedron Lett. 1992, 33, 6679.
Hale, K. J.; Grabski, M.; Manaviazar, S.; Maczka, M. Org. Lett. 2014, 16, 1164.
Spicer, J. A.; Rewcastle, G. W.; Kaufman, M. D.; Black, S. L.; Plummer, M. S.; Denny, W. A.; Quin, J.;
Shahripour, A. B.; Barrett, S. D.; Whitehead, C. E.; Milbank, J. B. J.; Ohren, J. F.; Gowan, R. C.; Omer, C.;
Camp, H. S.; Esmaeil, N.; Moore, K.; SeboltꢀLeopold, J. S.; Pryzbranowski, S.; Merriman, R. L.; Ortwine,
D. F.; Warmus, J. S.; Flamme, C. M.; Pavlovsky, A. G.; Tecle, H. J Med Chem 2007, 50, 5090.
Roth, P. J.; Wiss, K. T.; Zentel, R.; Theato, P. Macromolecules 2008, 41, 8513.
Sarkar, S. M.; Wanzala, E. N.; Shibahara, S.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Chem. Commun.
2009, 5907.
(24)
(25)
(26)
(27)
(28)
(29)
(30)
Nakano, A.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Org. Lett. 2006, 8, 5357.
Lankalapalli, R. S.; Ouro, A.; Arana, L.; GomezꢀMunoz, A.; Bittman, R. J. Org. Chem. 2009, 74, 8844.
Yang, G.; Schmieg, J.; Tsuji, M.; Franck, R. W. Angew. Chem. Int. Ed. 2004, 43, 3818.
Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507.
Conway, T. T.; DeMaster, E. G.; Goon, D. J. W.; Shirota, F. N.; Nagasawa, H. T. J Med Chem 1999, 42,
4016.
(31)
(32)
(33)
(34)
Seo, J.; Michaelian, N.; Owens, S. C.; Dashner, S. T.; Wong, A. J.; Barron, A. E.; Carrasco, M. R. Org. Lett.
2009, 11, 5210.
Carrasco, M. R.; Nguyen, M. J.; Burnell, D. R.; MacLaren, M. D.; Hengel, S. M. Tetrahedron Lett. 2002, 43,
5727.
Matsubara, N.; Oiwa, K.; Hohsaka, T.; Sadamoto, R.; Niikura, K.; Fukuhara, N.; Takimoto, A.; Kondo, H.;
Nishimurar, S. Chem-Eur J 2005, 11, 6974.
Wiltshire, H. R.; Prior, K. J.; Dhesi, J.; Trach, F.; Schlageter, M.; Schonenberger, H. J. Labelled Compd.
Radiopharm. 1998, 41, 1103.
(35)
Tedjamulia, T. D.; Srivastava, P. C.; Knapp, Jr. F. F. J. Med. Chem. 1985, 28, 1574.
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