Expanding the Boxmi Ligand Family: Synthesis and Application of NON and NSN Ligands

Article abstract of DOI:10.1021/acs.joc.0c00751

Two synthetic strategies for a new family of neutral NON ligands featuring a bis(oxazolinylmethylidene)isobenzofuran framework (boxman) are reported. A Pd-mediated cyclization reaction forming the isobenzofuran core constitutes the key reaction in the eight-step synthetic route to the nonbackbone-methylated target compound H,Rboxman. In contrast, the introduction of two additional methyl groups provides stereochemical control during backbone construction and thereby access to the methylated derivative Me,Rboxman, which was synthesized in five steps and improved yields. In addition, the synthetic sequence was transferred to the thio analogue, providing access to the NSN ligand H,Rboxmene. Subsequent complexation experiments with iron and cobalt chloride precursors afforded the four-coordinated chlorido complexes Me,RboxmanMCl2 (R = Ph, iPr; M = Fe, Co) and established the boxman family as trans-chelating, bidentate bis(oxazoline) ligands. Application of the latter in the nickel(II)- and zinc(II)-catalyzed α-fluorination of β-ketoesters and oxindoles (up to 98percent yield and 94percent ee) demonstrated their suitability for enantioselective catalysis.

Full text of DOI:10.1021/acs.joc.0c00751

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Article
Expanding the Boxmi Ligand Family: Synthesis
and Application of New NON and NSN Ligands
Clemens Blasius, Bing-Tao Ren, David Bürgy, Yan-Kai Liu, Bin Li,
Ina Michalsky, Hubert Wadepohl, Qing-Hai Deng, and Lutz H. Gade
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00751 • Publication Date (Web): 14 Apr 2020
Downloaded from pubs.acs.org on April 16, 2020
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Expanding the Boxmi Ligand Family: Synthesis and
Application of NON and NSN Ligands
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Clemens K. Blasius,† Bing-Tao Ren,‡ David Bürgy,† Yan-Kai Liu,‡ Bin Li,‡ Ina Michalsky,†
Hubert Wadepohl,† Qing-Hai Deng,*‡ Lutz H. Gade*†
†Anorganisch-Chemisches Institut, Universität Heidelberg, Im Neuenheimer Feld 270, 69120
Heidelberg (Germany), Fax: (+49)6221545609.
‡ The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare
Earth Functional Materials, Shanghai Normal University, Shanghai 200234, P. R. China.
E-Mail: qinghaideng@shnu.edu.cn; lutz.gade@uni-heidelberg.de.
Graphical Abstract
Abstract:
Two synthetic strategies for a new family of neutral NON ligands featuring a
“bis(oxazolinylmethylidene)isobenzofuran” framework (boxman) are reported. A Pd-mediated
cyclization reaction forming the isobenzofuran core constitutes the key reaction in the eight-step
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synthetic route to the non-backbone-methylated target compound H,Rboxman. In contrast,
introduction of two additional methyl groups provides stereochemical control during backbone
construction and thereby access to the methylated derivative Me,Rboxman, which was synthesized
in five steps and improved yields. In addition, the synthetic sequence was transferred to the thio
analogue, providing access to the NSN ligand H,Rboxmene. Subsequent complexation experiments
with iron and cobalt chloride precursors afforded the four-coordinated chlorido complexes
Me,RboxmanMCl2 (R = Ph, iPr; M = Fe, Co) and established the boxman family as trans-
chelating, bidentate bis(oxazoline) ligands. Application of the latter in the nickel(II)- and zinc(II)-
catalyzed -fluorination of -ketoesters and oxindoles (up to 98% yield and 94% ee)
demonstrated their suitability for enantioselective catalysis.
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Introduction
The success of transition-metal catalyzed asymmetric synthesis is inherently connected to the
development of stereodirecting ligands which ensure the efficient transfer of chirality. As a
consequence, extensive research in this field has given rise to numerous classes of privileged
ligand structures,1 ranging from chiral phosphines and NHCs to alcohols and salen-derivatives.2
However, the use of oxazolines as chiral structural units has been of particular interest due to
their facile preparation from amino alcohols and their efficient stereoinduction in asymmetric
transformations.3 With notable exceptions like the phox ligand,4 C2-symmetric bisoxazoline
ligands, in particular, emerged as a versatile class of ligands for a wide range of reactions.5
Nowadays, this group of ligands includes prominent examples such as pybox,6 box,7 dbfox8 and
boxmi9 (Figure 1). Apart from the two oxazoline cycles as common structural elements, these
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ligands vary with respect to the type and length of bridging elements, resulting in polydentate
stereodirecting ligands with different denticities, charges and chelating angles.
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Figure 1. Recent Examples for NNN- and NON-Bisoxazolinyl Ligands and Work Presented
in this Study
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Previous Tridentate Bisoxazolinyl (NNN) and (NON) ligands
R
O
O
O

O


N
N
R
R




N
N
N
N
R
R
R
R
NH
O
N
O
N
N

O
O
O
O
R
bopa
bopa analog
pybox
dbfox
Nishiyama
Guiry
Gómez
2002
Kanemasa
1989
2002
1997
O
O
O


R
R



N
R
R
N
R
R
N
NH
O
NH
N
N

N
O
O
O
cbzbox
boxmi
furmebox
Nakada
Gade
Gade
2003
2011
2013
This work
O
Synthesis of NON and NSN Ligands &
R'
R'
Asymmetric Fluorination of -Ketoesters:


R
N
E
R',Rboxman
O
O
F
Ni
Zn
]
[
] or [
N
R

CO2R2
CO2R2

F
N SI
O
R1
R1
R',R
R',R
O
1
boxman ( )
E =
E =
:
up to 94% yield
up to 93% ee
S
2
boxmene ( )
:
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Whereas both aliphatic links in neutral NN ligands (e.g. box, spirobox10) and a central
nitrogen donor in (monoanionic) tridentate NNN bisoxazoline ligands (e.g. pybox, cbzbox,11
bopa,12 pyrrmebox,13 boxmi) are well established, the incorporation of an oxygen atom as central
donor remains rare. In fact, to the best of our knowledge, the oxygen analog of bopa14 as well as
the ligands furmebox15 and dbfox are the only existing examples exhibiting these structural
characteristics (Figure 1). The dbfox ligand was found to induce high enantiomeric excesses in
various Lewis acid-catalyzed reactions such as the -fluorination of -ketoesters.16
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In recent studies, we reported the synthesis of “bis(oxazolinylmethylidene)isoindolines”,9
boxmi-H, and demonstrated their potential as a stereodirecting ligand platform in a range of 3d
metal-catalyzed transformations.17 Motivated by the success of the dbfox ligand and other neutral
compounds as well as our previous boxmi-related work, we aimed at combining the structural
properties of that ligand system with a neutral central donor. This led us to the preparation of the
oxygen and sulfur analogues of the established boxmi framework, namely to the synthesis of the
ligands bis(oxazolinylmethylidene)isobenzofuran (“boxman”) and –thiophene (“boxmene”). As
part of this study, we demonstrate two synthetic strategies towards boxman as well as an adapted
synthetic route to boxmene, a first brief evaluation of their coordination chemistry to 3d metals,
and their application as stereodirecting ligands in the -fluorination of -ketoesters and oxindoles
(Chart 1).
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Results and Discussion
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Initial Approach for Backbone Construction of boxman.
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Following our synthetic strategy for the synthesis of the monoanionic NNN pincer ligand boxmi-
H,9 we started our investigations by employing standard Wittig conditions for the construction of
the backbone. Reacting phthalic anhydride (3a) and thioloanhydride (4) with Wittig reagent 5
resulted in isomeric mixtures of the corresponding (Z,Z)-, (E,Z)- and (E,E)-products 6a and 7
(Scheme 1).18 Interestingly, whereas only the synthetically useless isomers (E,Z)-6a and (E,E)-6a
were formed for the oxygen derivative 6, the selective formation of the desired diester (Z,Z)-7
was observed when employing the sulfur analogue (for details see below). This necessitated an
alternative route to the target NON ligand which is presented below.
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Scheme 1. Initial Wittig Reaction for Backbone Preparation
EtO2C
EtO2C
CO2Et
CO2Et
O
CO2Et
( , 5.0 eq)
Ph3P
5
E
E
E
E
1,4-Dioxan, 120 °C,
3
4
12 h ( ) / 24 h ( )
O
CO2Et
EtO2C
3
4
(E = O)
(E = S)
(Z,Z)
(E,Z)
(E,E)
E = O: 6a
E = S: 7
0%
19%
15%
0%
11%
0%
Synthesis of NON Ligand H,Phboxman.
In view of the stereochemical issues accompanied with the Wittig reaction with phthalic
anhydride, we first focused on the development of an alternative route to prepare the ligand
backbone (Scheme 2).
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Scheme 2. Synthesis of H,Phboxman 1a
O
5
6
7
8
CO2Me
CO2H
I
CO2Me
OH
1) (COCl)2 (1.1 eq), DCM, rt, 4 h
(4.0 eq)
O
2) MeOAc (4.0 eq), LDA (1.5 eq)
Et2O, 72 °C, 8 h
Pd(PPh3)4 (5 mol%), CuI (10 mol%)
NEt3 (3.0 eq), THF, 50 °C, 18 h
I
CH2OH
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9
9 70%
10 86%
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Dess-Martin's
reagent (1.0 eq)
DCM, 0 °C, 20 h
CO2H
O
CO2Me
CO2Me
KOH (5 eq)
NaClO2 (4.0 eq), NaH2PO4 (6.0 eq)
O
O
EtOH/H2O, rt, 4 h
tBuOH/H2O, rt, 8 h
(COCl)2 (2.2 eq)
DMF (cat.)
CO2H
CO2H
CHO
13a 53%
11 90%
12 93%
DCM, rt, 3 h
O
O
Ph
Ph
Ph
NH2
COCl
PPh3 (5.0 eq), NEt3 (5.0 eq)
CCl4 (5.0 eq)
Ph
Ph
N
N
H
HO
OH
OH
(2.2 eq)
O
O
O
H
N
MeCN, 0 °C, 10 h
NEt3 (2.2 eq),
DCM, 0 °C, 24 h
N
COCl
O
O
1a 20%
H,Phboxman
14a
15a
60%
not isolated
Starting with 2-iodobenzoic acid (8), chlorination and subsequent Claisen-type condensation with
methyl acetate led to the formation of -ketoester 9 in 70% yield. The following Pd-catalyzed, O-
nucleophilic intramolecular heterocyclization reaction under comparatively mild conditions then
provided access to the isobenzofuran core, constituting the key step for the synthesis of
H,Phboxman (1a): Pd-catalyzed Sonogashira coupling of propargyl alcohol and subsequent
cyclization between carbonyl and alkyne moiety gave compound 10 in 86% yield. It is interesting
to note that ethyl propiolate could also be used for the isobenzofuran formation, resulting
immediately in desired diester 6a (see Scheme 1). However, low activities and limited scalability
of the reaction impeded the further development of this direct approach to a generally applicable
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synthetic protocol. Instead, conversion of alcohol 10 to acid 12 was achieved in a stepwise
fashion employing Dess-Martin and Pinnick oxidation reactions. As direct amidation attempts of
the carboxylic groups turned out not to be effective, the mixed acid ester 12 was first treated with
potassium hydroxide and then transformed into acid chloride 14a. The latter could readily be
converted into diamide 15a upon reaction with 2-phenylglycinol under basic conditions. Finally,
ring closure exploiting an Appel-type cyclization protocol19 with PPh3/NEt3/CCl4 yielded the
neutral NON ligand H,Phboxman (1a) in 20% yield.
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Alternative Synthesis of NON Ligand Me,Rboxman.
With a successful synthetic route for H,Phboxman (1a) in hand, we were interested in a more direct
strategy towards the latter due to the great effort – 8 steps in total – associated with ligand
synthesis according to Scheme 2. Reconsidering our initial approach for the construction of the
ligand backbone, we envisioned that steric control through an appropriate substitution pattern in
the backbone should in principle allow us to circumvent the aforementioned stereochemical
problems (Scheme 3).
In fact, introduction of two methyl groups in 2,6-dimethylphthalic anhydride20 led to the
exclusive formation of (Z,Z)-6b when subjected to standard Wittig conditions. Applying the very
same reaction sequence as before, we were able to convert diester 6b into diamide 15 in three
steps with significantly improved yields. As Appel-type reaction conditions for the final
cyclization produced inseparable side products, we eventually employed (diethylamino)sulfur
trifluoride (DAST) as cyclization reagent for the final step.21 Contrarily, this cyclization method
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turned out not to be applicable to the non-methylated derivative 1a, illustrating the sensitivity of
the given system with respect to final oxazoline synthesis.
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Scheme 3. Synthesis of Me,Rboxman (1b and 1c)
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O
CO2Et (5.0 eq)
1,4-Dioxan, 120 °C, 6 d
Ph3P
O
O
COX
O
6b
(X = OEt, 49%)
(X = OH, 90%)
(X = Cl, quant.)
3b
i)
13b
14b
ii)
iii)
O
O
R
R
R
N
N
OH
OH
H
DAST (2.2 eq)
O
O
H
N
DCM, 0 °C, 23 h
N
R
O
O
1b
1c
R=Ph: 38%
R=iPr: 65%
15b
15c
R=Ph: 69%
R=iPr: 87%
Reaction conditions: i) KOH (10 eq.), EtOH/THF/H2O, rt, 4 h; ii) (COCl)2 (2.2 eq.), DMF (cat.), DCM, 0 °C, 3 h; iii)
(S)-amino alcohol (2.5 eq.), NEt3 (2.5 eq.), DCM, 0 °C, 24 h.
In this way, the backbone-methylated NON ligands Me,Rboxman (1b,c) were readily synthesized
and obtained in good yields (R = Ph: 38%, R = iPr: 65%). All in all, this synthetic strategy is a
considerable improvement compared to above-mentioned initial route in terms of practical
feasibility and synthetic accessibility at the expense of a slight structural modification.
Synthesis of NSN Ligand H,Rboxmene.
Having established an effective route to NON ligands R’,Rboxman, we then aimed at extending
this synthetic concept to the sulfur derivative, R’,Rboxmene (2). Regarding the general strategy,
early-stage sulfur introduction and subsequent functionalization according to the oxygen
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congener 1 was chosen as reasonable approach (Scheme 4). In this context, the starting material 4
for the analogous synthesis is readily available from the reaction of phthalic anhydride with
sodium sulfide.22 Intriguingly, this initial oxygen-sulfur exchange reaction turned out to be only
applicable to the synthesis of the non-methylated derivative 3a, but not to 2,6-dimethylphthalic
anhydride. However, as mentioned above, the thioloanhydride 4 surprisingly proved suitable for
directly accessing (Z,Z)-7 (see Scheme 1), the absolute configuration of which was additionally
confirmed by X-ray diffraction (for details see SI).
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Scheme 4. Synthesis of H,Rboxmene (2)
COX
O
1) Na2S · 9 H2O
O
S
2)
CO2Et (5.0 eq)
Ph3P
O
COX
1,4-Dioxan, 120 °C, 20 h
3a
7
(X = OEt, 19%)
(X = OH, 79%)
(X = Cl, quant.)
i)
16
17
18
ii)
iii)
(X = NHCHRCH2OH,
R = Ph: 92%, R = iPr: 65%)
iv)
O
R
R
N
S
N
O
2a
R=Ph: 53%
2b R=iPr: 49%
Reaction conditions: i) KOH (10 eq.), EtOH/THF/H2O, rt, 4 h; ii) (COCl)2 (5.0 eq.), DMF (cat.), DCM, 0 °C, 3 h; iii)
(S)-amino alcohol (2.5 eq.), NEt3 (2.5 eq.), DCM, 0 °C, 20 h. iv) DAST (2.8 eq.), DCM, 0 °C, 3 h.
Interestingly, the sulfur analogue 4 displayed an increased reactivity in the Wittig coupling and
required only one day at 120 °C for complete conversion, which is in notable contrast to a
reaction time of 6 d at the same temperature in case of phthalic anhydride (see Scheme 3). From a
practical point of view, thiophthalic anhydride (4) could be prepared in situ and subjected to the
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Wittig reaction without prior purification giving compound (Z,Z)-7 in an overall 19% yield.
Subsequently, all previous reaction conditions found for the preparation of Me,Rboxman could also
be applied to the synthesis of H,Rboxmene in similar yields.
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Ligand Characterization.
The ligands were comprehensively characterized by NMR spectroscopy and mass spectrometry.
In addition, single-crystal X-ray structure analyses were carried out in order to confirm the (Z,Z)
configuration and to determine structural details of this new ligand class (see SI). In the solid
state structure of Me,Phboxman, the N-donors at the oxazoline units point away from the
isobenzofuran core, highlighting a certain degree of internal flexibility of these ligands.
Regarding the sulfur derivative, the solid-state structure revealed a preorganized orientation of
the donor atoms and the C2-chiral character of this ligand framework. In both cases, the oxazoline
rings align almost coplanar with the central isobenzofuran fragment, showing only slight torsions.
Synthesis of boxman Metal Complexes.
With these neutral NON and NSN ligands in hand, we carried out a first study of their
coordination chemistry in 3d metal complexes. Following our previous work on earth-abundant
metal-catalyzed stereoselective catalysis,17 we chose iron and cobalt for initial complexation
reactions. Moreover, the absence of stereoelectronical preferences in d6 and d7, respectively,
high-spin complexes allows for an exclusive evaluation of the coordinating properties of the
ligands in question. In this context, treating (thf)xMCl2 (M = Fe, Co) precursors with one
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equivalent of Me,Rboxman (R = Ph, iPr) in tetrahydrofuran yielded the respective
Me,RboxmanMCl2 complexes 19-20 as colored solids in good yields (Scheme 5).
Scheme 5. Synthesis of Metal Complexes Me,RboxmanMCl2 (19-20)
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O
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R
R
R
Cl
N
N
(thf)xMCl2 (1.0 eq.)
THF, rt, 1 d
O
O
M
Cl
R
N
N
O
O
1b
1c
19a
19b
20a
20b
(R = Ph)
(M = Fe, R = Ph, 63%)
(M = Fe, R = iPr, 64%)
(M = Co, R = Ph, 91%)
(M = Co, R = iPr, 84%)
(R = iPr)
In all cases, moderately-resolved paramagnetic H and 13C NMR spectra with comparatively
small shift dispersions were observed, indicating the presence of one well-defined complex
species in each case (SI). The magnetic susceptibilities in solution of these paramagnetic chlorido
complexes were determined employing the Evans method,23 and found to be in good agreement
with the respective spin-only values (µSO = 4.90 µB for d6, and 3.87 µB for d7 high-spin
complexes, respectively) for high-spin configurations in complexes 19 and 20.
1
In addition to these characteristic features in solution, the molecular structures in the solid-state
were established by X-ray diffraction (Figure 2). Interestingly, the metal centers were found to be
four-coordinate in both cases, exhibiting a distorted tetrahedral coordination sphere with the
metal atoms positioned significantly above the plane of the donor atoms of the boxman ligand
(dMplane = 0.969(3) to 1.042(1) Å). Whereas the M–N bond lengths for the oxazoline groups are
in accordance with similar compounds reported in literature, the M–O distances in the range of
dMO = 2.442(2) to 2.557(3) Å indicate the absence of significant bonding interactions between
the central oxygen donor and the metal atom, thus establishing the boxman framework as a trans-
chelating bidentate ligand in the given context. These structural characteristics demonstrate
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distinct difference between boxman complexes and comparable boxmi based compounds,9, 17e, 17g,
24 in which a meridional coordinating and structurally rigid ligand was observed in all cases.
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Figure 2. Molecular structures of iron and cobalt complexes 19b (left) and 20b (right) in the
solid state. Hydrogen atoms have been omitted for clarity; displacements ellipsoids are set at 50%
(19b) and 30% (20b) probability level; only one of the two independent molecules is shown for
20b. Selected bond lengths [Å] and angles [°], values for the second independent molecules are
given in square brackets: 19b: FeN1 2.0832(18); FeN2 2.0995(18); FeCl1 2.3427(6); FeCl2
2.2923(6); Fe-O2 2.4423(15); N1FeN2 120.14(7); Cl1FeCl2 107.56(2); N1C3C4C5
15.8(4); C12C13C14N2 17.1(4); 20b: CoN1 2.062(4) [2.063(3)]; CoN2 2.051(4)
[2.055(4)]; CoCl1 2.2911(12) [2.2928(12)]; CoCl2 2.2814(12) [2.2811(13)]; Co-O2 2.515(3)
[2.521(3)]; N1CoN2 121.92(15) [122.93(14)]; Cl1MCl2 108.04(5) [110.61(5)];
N1C3C4C5 .5(8) [16.3(8)]; C12C13C14N2 27.3(9) [31.2(8)].
In a next step, we focused on investigating further binding modes of the neutral NON ligands
R’,Rboxman. In this context, we treated chlorido complex 20b with the chloride abstracting agent
AgOTf (silver triflate), leading to a change of color from cyan to purple-blue (Scheme 6).
Scheme 6. Generation of Ditriflato Complexe Me,iPrboxmanCo(OTf)2 (21)
O
O
iPr
iPr
iPr
OTf
N
N
AgOTf
Cl
Cl
O
Co
O
Co
OTf
iPr
DCM, rt, 3 h
N
N
O
O
20b
21
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The isolation of the reaction product turned out to be difficult due to the formation of unknown
impurities and concomitant ligand dissociation. We were, however, able to obtain single crystals
of a methylene chloride solvate of the product which was identified by X-ray diffraction as the
ditriflato complex 21 (Figure 3). Due to mediocre crystal quality, disorder and the presence of no
less than eight independent molecules only the salient features of the structure are discussed. A
distorted trigonal-bipyramidal coordination sphere around the cobalt center is observed for
complex 21. The CoO distance is significantly shortened (dCoO = 2.316(9)-2.362(8) Å) and the
cobalt atom is located in closer proximity to the plane of the donor atoms of the boxman ligand
10
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(dCoplane = 0.803(8)-.885(8) Å) compared to the respective chlorido complex (for 20b: dCoO
=
2.515(3) [2.521(3)] Å, dCoplane = 0.991(3) [0.975(3)] Å). In view of an averaged CoO bond
= 2.117(6) Å in Co·(thf) complexes,25 these findings demonstrate only a
length of dCo–O(thf)
̅
relatively weak interaction between the cobalt center and the central isobenzofuran core.
Figure 3. Molecular structure of the ditriflato complex 21 in the solid state. Hydrogen atoms
have been omitted for clarity; displacements ellipsoids are set at 50% probability level; only one
of the eight independent molecules in 21·0.25 CH2Cl2 is shown. Selected bond lengths [Å] and
angles [°], given as range for all independent molecules: CoN1 1.978(11)-2.005(11); CoN2
1.964(12)-2.016(12); CoO2 2.316(9)-2.362(8); CoO4 1.992(10)-2.032(10); CoO7 1.963(10)-
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2.002(9); N1CoN2 127.3(5)-132.4(5); O2CoO4 172.6(4)-178.7(4); O2CoO7 79.8(4)-
89.0(4); N1C3C4C5 (3)-(3)); C12C13C14N2 (3)-21(3).
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8
9
Ni- and Zn-Catalyzed Fluorination of Ketoesters and Oxindoles.
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Having established the coordination chemistry of boxman ligands in iron and cobalt metal
complexes, we then aimed at evaluating their stereodirecting performance in catalytic
transformations. With the appearance of 1 in metal complexes as trans-chelating, bidentate
ligand, we envisioned the application of preferably square-planar coordinated metals as
prerequisite for this objective. Therefore, we chose the Lewis acid catalyzed asymmetric
fluorination of β-ketoesters and oxindoles with N-fluorobenzenesulfonimide (NFSI) as test
reaction,16 for which we previously observed excellent yields and enantioselectivities when
employing the related boxmi ligand (Table 1).9
Table 1. Optimization of Reaction Conditions for the Nickel-Catalyzed Fluorination of
Ketoester 22a
Lig
NiX2 (10 mol%),
(11 mol%)
O
O
NFSI (1.2 eq.), MS 4Å
F
O
O

solvent, rt, 16 h
OtBu
OtBu
F
F
standard conditionsa
23a
22a
#
1
2
3
4
5
6
7
varied conditionb
none
% yieldc
>95
% eed
93
salt: Ni(OTf)2
>95
90
salt: Ni(NTf2)2
salt: Ni(dme)Cl2
salt: Ni(OAc)2
salt: Ni(ClO4)2 ·6 H2O
ligand: Me,iPrboxman
>95
89
>95
88
n.d.e
>95
41
76
>95
59
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solvent: n-pentane
solvent: toluene
solvent: Et2O
n.d.
>95
n.d.
n.d.
n.d.
15
91
41
20
22
9
10
11
solvent: THF
12
solvent: MeCN
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a
standard conditions: substrate 22a (40 µmol, 1.0 eq.), N-fluorobenzenesulfonimide (1.2 eq.), Ni(ClO4)2 (10 mol%), Me,Phboxman (11 mol%),
molecular sieve 4 Å, dichloromethane, room temperature, 16 h.
b deviation from standard condition; unless indicated otherwise.
c determined by 19F NMR spectroscopy of the reaction mixture.
d determined by HPLC analysis.
e not determined.
Starting with the previously reported standard conditions and the readily available ligands
Me,Rboxman 1b,c, nickel perchlorate in combination with Me,Phboxman gave near-quantitative
conversion of test substrate 22a and an excellent enantiomeric excess of 93% ee (entry 1). The
use of (dimethoxyethane) nickel dichloride ((dme)NiCl2) as well as other anhydrous nickel salts
with weakly coordinating anions resulted in similar stereoinduction (entries 2-6). In contrast,
substantial differences in stereoselectivity were obtained when modifying the oxazoline
substituent as a change from Ph to iPr led to a dramatically reduced enantiomeric excess (entry
7). In addition, solvent screening indicated only toluene and dichloromethane as suitable solvents
(entries 8-12). Monitoring the reaction progress by 19F NMR spectroscopy, we found that
reducing the reaction temperature below room temperature or the catalyst loading below
10 mol% would lead to impractically long reaction times.
In a next step, we focused both on extending the scope of the reaction and on a comparison of the
ligand structures developed in this work (Table 2). Regarding further metal salts, the use of
copper salts led to racemic mixtures (entry 2), whereas zinc bistriflimide was found to provide
similarly high stereoselectivities as nickel salts (entry 3).
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Table 2. Optimization of Reaction Conditions for the Fluorination of Ketoester 22b
5
6
O
O
M
Lig
(12 mol%)
X2 (10 mol%),
F
O
O
NFSI (2.0 eq.)
7

OtBu
OtBu
DCM, rt, 4 h
8
9
22b
23b
10
11
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#
Metal salt
Ligand
% yield
93
% eeb
82
1
1c Ni(ClO4)2 ·6 H2O H,Phboxman
2c Cu(OTf)2
H,Phboxman
H,Phboxman
96
3
4
5
Zn(NTf2)2
Zn(NTf2)2
Zn(NTf2)2
90
92
90
9
Me,Phboxman 60
H,Phboxmene 36
a reaction conditions: substrate 22b (0.10 mmol), N-fluorobenzenesulfonimide (2 eq.), metal salt (10 mol%), ligand (12 mol%), dichloromethane
(1.0 mL), room temperature, 4 h.
b determined by HPLC analysis.
c 5 h reaction time.
Upon altering the ligand from H,Phboxman to the backbone methylated derivative Me,Phboxman,
only subtle changes in enantiodiscrimination were observed (entry 4) for the Zn-catalyzed
fluorination. On the other hand, employment of the sulfur analogue H,Phboxmene rendered the
fluorinated reaction product with only a marginal enantiomeric excess.
Having determined the ideal conditions for the catalytic systems, we proceeded to screen a range
of suitable substrates for both the nickel(II)- and zinc(II)-catalyzed enantioselective fluorination
(Scheme 7). Generally high yields and stereoselectivities demonstrated the applicability of our
catalytic system.
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Scheme 7. Substrate Scopes for the Nickel(II) and Zinc(II)-catalyzed Fluorination of β-
5
6
Ketoesters
7
8
9
O
O
M
X2 (10 mol%)
R',Phboxman
F
O
O
(11-12 mol%)
NFSI (1.2-2.0 eq.)
DCM, rt, t
R1
R1

OR2
OR2
10
11
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22
23
Nickel(II)-catalysisa
O
O
O
Cl
F
F
F
O
O
O



OtBu
OtBu
OtBu
F
Br
23a
93%, 93% ee
23c
45%, 89% ee
23d
97%, 92% ee
O
O
O
MeO
MeO
MeO
MeO
MeO
MeO
F
F
F
O
O
O
O



OtBu
OMe
23e
98%, 94% ee
23f
23g
98%, 64% ee
89%, 57% ee
Zinc(II)-catalysisb
O
O
O
F
F
F
O
O
O



OtBu
OtBu
OtBu
Cl
Br
23b
90%, 92% ee
23h
90%, 84% ee
23c
85%, 87% ee
a reaction conditions: substrate 22 (0.1 mmol), N-fluorobenzenesulfonimide (1.2 eq.), Ni(ClO4)2 (10 mol%), Me,Phboxman (11 mol%), molecular
sieves (4 Å), dichloromethane (1.0 mL), room temperature, 16 h.
reaction conditions: substrate 22 (0.1 mmol), N-fluorobenzenesulfonimide (2.0 eq.), Zn(NTf)2 (10 mol%), H,Phboxman (12 mol%),
b
dichloromethane (1.0 mL), room temperature, 5 h.
c enantiomeric excess determined by HPLC analysis.
Whereas backbone substitution of the ketoester appeared to have only moderate influence
on the reaction outcome (R1 = F, Cl, Br, Me, MeO), the steric bulk of the ester group turned out
to be a key prerequisite for a successful functionalization: exchanging the tert-butyl moiety for
ethyl and allyl groups resulted in high conversions, but significantly reduced enantioselectivities.
Given the structural resemblance of oxindoles and β-ketoesters, we also applied our standard
protocol to three derivatives of this class of substrates. Overall, inferior results in terms of yield
and stereoselectivity were obtained for oxindoles compared to β-ketoesters (Scheme 8) whereas
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the same general trends were found: backbone substitution had no major influence on the
5
6
enantioselectivity, while steric bulk of the protecting group (boc versus acetyl) was vital.
7
8
9
Scheme 8. Substrate Scope for the Nickel-catalyzed Fluorination of Oxindolesa
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R1
R1
Ni(ClO4)2 (10 mol%)
Me,Phboxman (11 mol%)

F
O
O
NFSI (1.2 eq.), MS 4Å
DCM, rt, 16 h
N
N
R2
24
R2
25
Fluorination of Oxindoles
Me
OMe



F
F
F
O
O
O
N
N
N
Boc
25a
41%, 73% ee
Boc
Ac
25c
87%, 25% ee
25b
71%, 79% ee
a enantiomeric excess determined by HPLC analysis.
Conclusions
In conclusion, the class of stereodirecting bis(oxazoline) ligands has been extended by two
further representatives, namely the NON ligand “bis(oxazolinylmethylidene)isobenzofuran”,
R’,Rboxman, and its thio derivative boxmene. In case of R’,Rboxman, the stereochemial issues
R
accompanied with initial backbone construction were either resolved by a Pd-catalyzed
heterocyclisation reaction (R’ = H, 8 steps in total) or by means of the introduction of
stereodirecting methyl groups (R’ = Me, 5 steps overall). The effective use of these trans-
chelating ligands in the nickel(II)- or zinc(II)-catalyzed -fluorination of carbonyl substrates has
provided first evidence of their potential in stereoselective catalysis and prompts further
applications in 3d metal catalysis.
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Experimental Section
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Unless stated otherwise, all manipulations were performed under dried argon in standard Schlenk
glassware, which was flame-dried prior to use. Solvents were dried according to standard
procedures. The 1H and 13C NMR spectra were recorded on Bruker Avance (400 MHz, 600 MHz)
instruments. Mass spectra were recorded by the mass spectrometry service of Shanghai Institute
of Organic Chemistry or at the mass spectrometry facility of the Institute of Organic Chemistry.
2,6-Dimethyl phthalic anhydride (3b)20 and ketoesters26 were synthesized according to literature
procedures. All other starting materials were obtained commercially and used without further
purification.
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Preparation of compound 9:
To a solution of 2-iodobenzoic acid (4.96 g, 20.0 mol, 1.0 eq.) in anhydrous DCM (80 mL) was
added oxalyl chloride (1.86 mL, 22.0 mol, 1.1 eq.) and 100 L DMF via syringe at room
temperature. After stirring the reaction mixture at room temperature for 4 h, all volatiles were
removed in vacuo to afford the raw product, which can be used without any further operation. In
a separate flask was added methyl acetate (6.36 mL, 80.0 mol, 4.0 eq.) to a solution of lithium
diisopropylamide (15 mL, 2 M in THF, 1.5 eq.) in anhydrous Et2O (100 mL) slowly at 72 °C.
The mixture was stirred for 20 min at this temperature, before a suspension of the acyl chloride in
Et2O (15 mL) was added very slowly. After stirring the mixture at 72 °C for 30 min, the
reaction was stopped by adding aqueous HCl (1 M, 100 mL). The product was extracted with
Et2O (2 x 100 mL) and the combined organic phases were washed with brine (50 mL) and dried
over sodium sulfate. Subsequently, the solvent was removed in vacuo and the crude product was
purified by column chromatography (petroleum ether/ethyl acetate = 35:1), affording the product
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as yellow oil (4.26 g, 14 mol, 70%). The product exists as a 1.7:1.0 mixture of ketone and enol
tautomers. Spectroscopic Data have been reported previously.27 1H NMR (400.20 MHz, CDCl3,
295 K): δ (ppm) = 12.27 (s, 0.5 H, enol), 7.94 (dd, J = 17.8, 7.9 Hz, 1 H, ketone), 7.91 (d, J = 7.8
Hz, 0.5 H, enol), 7.47 (ddd, J = 8.2, 7.5, 1.2 Hz, 2 H, ketone and enol), 7.40 (dd, J = 9.0, 2.0 Hz,
2 H, ketone and enol), 7.16 (td, J = 7.7, 1.7 Hz, 2 H, ketone), 7.14–7.06 (m, 0.5 H, enol), 5.36 (s,
0.5H, enol), 4.00 (s, 2 H, ketone), 3.82 (s, 1.7 H, enol), 3.74 (s, 3 H, ketone).
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Preparation of compound 10:
To a solution of compound 9 (6.08 g, 20.0 mmol, 1.0 eq.) in anhydrous THF (400 mL) were
added propargyl alcohol (4.6 mL, 80.0 mmol, 4.0 eq.), Pd(PPh3)4 (1.16 g, 1.0 mol, 5 mol%), CuI
(381 mg, 2.0 mol, 10 mol%) and Et3N (8 mL, 60.0 mmol, 3.0 eq.). The reaction mixture was
stirred at 50 °C for 8 h. Subsequently, the solvent was removed under reduced pressure and the
residue was purified by column chromatography (petroleum ether/ethyl acetate = 1:1) to afford
the product as yellow solid in (3.99 g, 17.2 mol, 86%). 1H NMR (400.20 MHz, CDCl3, 295 K): δ
(ppm) = 7.62 (d, J = 3.8 Hz, 1 H), 7.60 (d, J = 3.4 Hz, 1 H), 7.54 (t, J = 7.4 Hz, 1 H), 7.46 (t, J =
7.4 Hz, 1 H), 5.70 (t, J = 6.8 Hz, 1 H), 5.62 (s, 1 H), 4.66 (d, J = 6.8 Hz, 2 H), 3.80 (s, 3 H).
13C{1H} NMR (100.63 MHz, CDCl3, 295 K): δ (ppm) = 166.1, 162.0, 152.5, 134.1, 132.7, 131.7,
+
129.8, 121.2, 120.3, 103.5, 87.8, 57.2, 51.4. HRMS (EI+): calcd. for C13H12NaO4 [M+Na]+:
255.0628; found: 255.0627.
Preparation of compound 11:
To a solution of compound 10 (4.64 g, 20.0 mmol, 1.0 eq.) in anhydrous DCM (180 mL) at 0 oC
was added Dess–Martin periodinane (8.48 g, 20.0 mmol, 1.0 eq.). The reaction mixture was
stirred at 0 °C overnight, before aqueous Na2S2O3 (10%, 50 mL) and saturated NaHCO3 (50 mL)
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solutions were added. After 30 min, the suspension was filtered and the organic phase was
washed successively with a saturated NaHCO3 solution (100 mL) and brine (100 mL). The
organic phase was then dried over sodium sulfate and freed from any volatiles in vacuo. The
crude product was recrystallized from DCM/PE, affording the product as white solid (4.14 g,
18.0 mmol, 90%). 1H NMR (400.20 MHz, CDCl3, 295 K): δ (ppm) = 10.39 (d, J = 8.0 Hz, 1 H),
7.75-7.69 (m, 2 H), 7.64 (m, J = 7.2 Hz, 2 H), 5.94 (d, J = 8.0 Hz, 1 H), 5.82 (s, 1 H), 3.81 (s, 3
H). 13C{1H} NMR (100.63 MHz, CDCl3, 295 K): δ (ppm) = 189.0, 165.2, 164.8, 160.0, 133.5,
10
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+
133.0, 132.8, 132.3, 122.5, 121.6, 102.4, 92.7, 51.8. HRMS (ESI+): calcd. for C13H10NaO4
[M+Na]+: 253.0483; found: 253.0471.
Preparation of compound 12:
Under ambient conditions, compound 11 (4.60 g, 20.0 mmol, 1.0 eq.) was dissolved in tert-
BuOH (200 mL) and H2O (40 mL) and a solution of NaClO2 (7.40 g, 80.0 mmol, 4.0 eq.) and
NaH2PO4 (14.0 g, 120 mmol, 6.0 eq.) in 40 mL H2O was added very slowly at room temperature.
After stirring the mixture for 8 h, all volatiles were removed under reduced pressure. The residue
was diluted in 100 mL DCM and treated with 50 mL hydrochloric acid (1 M). The organic phase
was washed with water (200 mL) and dried over anhydrous sodium sulfate. Removal of the
solvent under reduced pressure afforded the raw product 12, which purified by recrystallization
1
from DCM/PE. The product was obtained as white solid (4.61 g, 18.7 mmol, 93%). H NMR
(400.20 MHz, DMSO- d6, 295 K): δ (ppm) = 12.31 (s, 1 H), 8.10 (dd, J = 8.5, 5.1 Hz, 2 H), 7.68
(dd, J = 8.5, 5.1 Hz, 2 H), 6.15 (s, 1 H), 6.07 (s, 1 H), 3.69 (s, 3 H). 13C{1H} NMR (100.63 MHz,
DMSO-d6, 295 K): δ (ppm) = 165.2, 164.1, 160.4, 159.4, 133.3, 133.0, 132.3, 132.1, 122.2,
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+
122.1, 93.4, 91.4, 51.1. HRMS (ESI+): calcd. for C13H10NaO5 [M+Na]+: 269.0420; found:
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269.0419.
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Preparation of compound 13a:
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Under ambient conditions, compound 12 (2.46 g, 10.0 mmol, 1.0 eq.) and KOH (2.80 g, 50.0
mmol, 5.0 eq.) were dissolved in a solution of ethanol (50 mL) and H2O (30 mL). The reaction
mixture was then stirred at room temperature for 4 h. After removing ethanol under reduced
pressure, hydrochloric acid (1 M) was added, until large amount of solid precipitated. The
suspension was filtered and the filter cake was dried in vacuo, affording the product as white
solid (1.24 g, 5.34 mol, 53%). 1H NMR (400.20 MHz, DMSO-d6, 295 K): δ (ppm) = 8.07 (dd, J =
13
5.8, 3.0 Hz, 2 H), 7.67 (dd, J = 5.8, 3.0 Hz, 2 H), 6.02 (s, 1 H). C{1H} NMR (100.63 MHz,
DMSO-d6, 295 K): δ (ppm) = 165.2, 159.5, 133.2, 132.0, 122.0, 92.9. HRMS (ESI+): calcd. for
+
C12H9O5 [M+H]+: 233.0444; found: 233.0447.
Preparation of compounds 15a:
To a solution of compound 13a (2.32 g, 10.0 mmol, 1.0 eq.) in anhydrous DCM (50 mL) was
added oxalyl chloride (1.27 mL, 22.0 mmol, 2.2 eq.) and 100 l DMF via syringe at room
temperature. The mixture was stirred at room temperature for 3 h. Subsequently, all volatiles
were removed in vacuo, affording the raw acyl chloride as brown solid. The residue was
redissolved in 15 mL anhydrous DCM and treated subsequently with triethylamine (3.06 mL,
22.0 mmol, 2.2 eq.) and 2-phenylglycinol (3.02 g, 22.0 mmol, 2.2 eq.) at 0 °C. After stirring the
reaction mixture at 0 oC for 24 h, water (20 mL) was added. The resulting mixture was extracted
with DCM (3 x 50 mL) and the combined organic phases were dried over magnesium sulfate.
The solvent was removed under reduced pressure and the crude product was purified by flash
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chromatography (petroleum ether/ethyl acetate = 4:1 to dichloromethane/ethanol = 10:1) to
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afford the product as white solid (2.82 g, 6.0 mmol, 60%). H NMR (400.20 MHz, DMSO-d6,
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8
9
295 K): δ (ppm) = 8.72 (d, J = 8.2 Hz, 2 H), 7.95 (dd, J = 5.7, 3.0 Hz, 2 H), 7.68 (dd, J = 5.7, 3.0
Hz, 2 H), 7.49–7.27 (m, 4 H), 7.29–7.08 (m, 6 H), 6.14 (s, 2 H), 5.02 (dd, J = 13.7, 8.0 Hz, 4 H),
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3.70 (td, J = 11.3, 4.8 Hz, 4 H). C{1H} NMR (100.63 MHz, DMSO-d6, 295 K): δ (ppm) =
163.5, 156.2, 141.3, 132.5, 132.0, 128.2, 127.2, 126.8, 121.8, 95.9, 64.7, 55.5. HRMS (ESI+):
calcd. for C28H26N2NaO5 [M+Na]+: 493.1734; found: 493.1737.
+
Preparation of compounds 1a:
To a solution of compound 15a (940 mg, 2.00 mmol, 1.0 eq.) in MeCN (50 mL) were added PPh3
(2.62 g, 10.0 mol, 5.0 eq.), Et3N (1.39 mL, 10.0 mol, 5.0 eq.) and CCl4 (966 l, 10.0 mmol, 5.0
eq.). The reaction mixture was stirred at 0 °C. After completion of the reaction (monitored by
TLC, about 10 h), water (100 mL) was added and the resulting mixture was extracted with DCM
(5 x 50 mL). The combined organic phases were dried over magnesium sulfate. The solvent was
removed under reduced pressure and the crude product was purified by flash chromatography
(petroleum ether/ethyl acetate = 1:1), affording the product as white solid (172 mg, 0.40 mmol,
1
20%). H NMR (400.20 MHz, CDCl3, 295 K): δ (ppm) = 7.69 (s, 2 H), 7.57 (s, 2 H), 7.33 (s,
10H), 6.06 (s, 2 H), 5.33 (t, J = 9.2 Hz, 2 H), 4.82 (t, J = 9.1 Hz, 2 H), 4.29 (t, J = 8.3 Hz, 2 H).
13C{1H} NMR (100.63 MHz, CDCl3, 295 K): δ (ppm) = 162.8, 157.7, 142.4, 133.6, 131.5, 128.8,
127.6, 126.9, 121.3, 88.9, 75.0, 69.7. HRMS (ESI+): calcd. for C28H22N2NaO3 [M+Na]+:
+
457.1523; found: 457.1522.
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Preparation of compound 6b:
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A mixture of 2,5-dimethylphthalic anhydride (5.14 g, 29.2 mmol, 1.0 eq.) and
(carbethoxymethylene)triphenylphosphorane (50.8 g, 146 mmol, 5.0 eq.) was suspended in 150
mL absolute 1,4-dioxane. After heating the reaction mixture to 120 °C for 6 d, the solvent was
removed in vacuo. The dark brown residue was purified by column chromatography (petroleum
ether/ethyl acetate = 5:1 → 3:1), yielding the product as a yellow solid (4.50 g, 14.2 mmol, 49%).
1H NMR (600.13 MHz, CDCl3, 295 K): δ (ppm) = 7.22 (s, 2 H), 5.79 (s, 2 H), 4.30 (q, J = 7.1
Hz, 4 H), 2.52 (s, 6 H), 1.37 (t, J = 7.1 Hz, 6 H). 13C{1H} NMR (150.90 MHz, CDCl3, 295 K): δ
[ppm] = 164.7, 161.2, 133.9, 132.7, 132.2, 95.8, 60.5, 20.5, 14.5. HRMS (EI+): calcd. for
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+
C18H20O5 [M]+: 316.1311; found: 316.12908.
Preparation of compound 13b:
Under ambient conditions, a solution of KOH (4.26 g, 75.9 mmol, 10.0 eq.) in 30 mL water was
added dropwise to a suspension of compound 6b (2.40 g, 7.59 mmol, 1.0 eq.) in 100 mL ethanol,
60 mL tetrahydrofuran and 30 mL water. The reaction mixture was stirred at room temperature
for 3-4 h forming a brown solution. Subsequently, the solvent was removed under reduced
pressure and the residue was redissolved in 300 mL water. The solution was acidified with
aqueous HCl (2M, about 30 mL), until a pH value of 2-3 was reached. The resulting precipitate
was filtered, washed with water and distilled azeotropically with toluene, affording the product as
an off-white solid (1.78 g, 6.84 mmol, 90%). 1H NMR (600.13 MHz, DMSO-d6, 295 K): δ (ppm)
= 12.13 (s, 2 H), 7.36 (s, 2 H), 5.69 (s, 2 H), 2.47 (s, 6 H). 13C{1H} NMR (150.90 MHz, DMSO-
d6, 295 K): δ [ppm] = 165.1, 159.5, 134.1, 132.5, 131.2, 96.0, 19.8. HRMS (EI+): calcd. for
+
C14H12O5 [M]+: 260.0685; found: 260.06694.
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Preparation of compound 14b:
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Carbonic acid 13b (1.50 g, 5.77 mmol, 1.0 eq.) was suspended in 250 mL dichloromethane.
Subsequently, oxalylchloride (1.61 g, 1.09 mL, 12.7 mmol, 2.2 eq.) and a catalytic amount of
N,N-dimethylformamide were added dropwise at 0 °C. The suspension was warmed to room
temperature over a period of 2-3 h, giving a dark red solution. The reaction mixture was freed
from any volatiles in vacuo to obtain the crude product in quantitative yield, which was used for
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subsequent reactions without further purification. H NMR (600.13 MHz, CDCl3, 295 K): δ
(ppm) = 7.40 (s, 2 H), 6.19 (s, 2 H), 2.59 (s, 6 H). 13C{1H} NMR (150.90 MHz, CDCl3, 295 K): δ
+
(ppm) = 161.7, 159.9, 135.8, 131.8, 102.0, 20.5. HRMS (EI+): calcd. for C14H10ClO3 [M-Cl]+:
261.0313; found: 261.03019.
Preparation of compound 15b:
Acid chloride 14b (1.15 g, 3.84 mmol, 1.0 eq) was dissolved in 120 mL dichloromethane and a
solution of triethylamine (971 mg, 1.34 mL, 9.59 mmol, 2.5 eq.) and (S)-2-phenylglycinol (1.32
g, 9.59 mmol, 2.5 eq.) in 10 mL dichloromethane was added dropwise at 0 °C. The reaction
mixture was stirred at 0 °C for 24 h. Approximately 2/3 of the solvent volume was then removed
under reduced pressure and the reaction was quenched by the addition of 80 mL water. The
resulting precipitate was filtered, washed with water and little dichloromethane, and dried in
1
vacuo, yielding the product as a colorless solid (1.31 g, 2.63 mmol, 69%). H NMR (600.13
MHz, DMSO- d6, 295 K): δ (ppm) = 8.91 (d, J = 8.2 Hz, 2 H), 7.37 (s, 2 H), 7.36-7.33 (m, 4 H),
7.23-7.18 (m, 6 H), 5.94 (s, 2 H), 5.05-5.01 (m, 2 H), 5.00 (t, J = 5.8 Hz, 2 H), 3.80-3.70 (m, 2
H), 3.74-3.68 (m, 2 H), 2.49 (s, 6 H). 13C{1H} NMR (150.90 MHz, DMSO- d6, 295 K): δ (ppm)
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= 163.8, 156.3, 141.5, 133.6, 132.3, 130.8, 128.1, 127.3, 126.8, 99.1, 64.6, 55.6, 19.6. HRMS
5
6
+
(EI+): calcd. for C30H31N2O5 [M+H]+: 499.2227; found: 499.2237.
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Preparation of compound 15c:
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A solution of L-valinol (790 mg, 7.66 mmol, 2.5 eq.) and triethylamine (1.07 mL, 7.66 mmol, 2.5
eq.) in 10 mL dichloromethane was added dropwise to a solution of acid chloride 14b (910 mg,
30.6 mmol, 1.0 eq.) in 100 mL dichloromethane at 0 °C. The red solution was then stirred at 0 °C
for 20 h, before it was concentrated to 1/5 of its volume and quenched with 70 mL water. The
reaction mixture was extracted with dichloromethane and the combined organic phases were
washed with water (3 x 50 mL) and dried over sodium sulfate. The solvent was reduced in vacuo
to 3-4 mL and treated with n-pentane, yielding a brown oil. The supernatant was removed and the
residue was purified by column chromatography (dichloromethane/methanol = 19:1). The
1
product was obtained as an off-white solid (1.15 g, 2.67 mmol, 87%). H NMR (600.13 MHz,
DMSO-d6, 295 K): δ (ppm) = 8.16 (d, J = 9.0 Hz, 2 H), 7.38 (s, 2 H), 5.92 (s, 2 H), 4.63 (t, J =
5.5 Hz, 2 H), 3.83-3.79 (m, 2 H), 3.54-3.52 (m, 4 H), 2.50 (s, 6 H), 1.97-1.89 (m, 2 H), 0.89-0.85
13
(m, 12 H). C{1H} NMR (150.90 MHz, DMSO-d6, 295 K): δ (ppm) = 163.9, 155.8, 133.3,
+
132.0, 130.8, 99.4, 61.5, 55.8, 28.6, 19.7, 19.6, 18.2. HRMS (ESI-): calcd. for C24H33N2O5 [M-
H]+: 429.2395; found: 429.2397.
Preparation of compound 1b:
A suspension of amide 15b (1.65 g, 3.31 mmol, 1.0 eq.) in 50 mL dichloromethane was treated
dropwise at 0 °C with diethylaminosulfur trifluoride (1.31 mL, 1.60 g, 9.93 mmol, 3.0 eq.). The
solution was stirred at 0 °C for 2.5 h and then quenched by adding 4 N aqueous ammonium
hydroxide solution (20 mL). The reaction mixture was extracted with dichloromethane and the
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combined organic phases were dried over sodium sulfate and purified by column chromatography
(silica gel was deactivated with triethylamine prior to use, petroleum ether/ethyl acetate = 2:1 →
0:1). The product is obtained as a yellow solid (575 mg, 1.24 mmol, 38%). Single crystals
suitable for X-ray diffraction analysis were obtained by layering a solution of the compound in
dichloromethane with toluene and n-pentane. 1H NMR (600.13 MHz, CDCl3, 295 K): δ (ppm) =
7.35-7.34 (m, 8 H), 7.29- 7.25 (m, 2 H), 7.23 (s, 2 H), 6.09 (s, 2 H), 5.32 (dd, J = 10.1 Hz, J = 8.9
Hz, 2 H), 4.80 (dd, J = 10.1 Hz, J = 8.3 Hz, 2 H), 4.27 (t, J = 8.6 Hz, 2 H), 2.57 (s, 6 H). 13C{1H}
NMR (150.90 MHz, CDCl3, 295 K): δ (ppm) = 163.5, 158.4, 142.5, 133.5, 132.3, 132.1, 128.8,
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+
127.7, 127.0, 92.3, 74.9, 69.7, 20.6. HRMS (ESI+): calcd. for C30H27N2O3 [M+H]+: 463.2016;
found: 463.2020.
Preparation of compound 1c:
Diethylaminosulfur trifluoride (1.78 mL, 2.17 g, 13.5 mmol, 4.0 eq.) was added dropwise at 0 °C
to a suspension of compound 15c (1.45 g, 3.36 mmol, 1.0 eq.) in 50 mL dichloromethane. After
stirring the mixture at 0 °C for 4 h, the reaction was stopped by adding aqueous ammonium
hydroxide solution (4 N, 20 mL). The product was purified by column chromatography (silica gel
was
deactivated
with
triethylamine
prior
to
use,
petroleum
ether/ethyl
acetate/dichloromethane/triethylamine = 4:1:1, 1% → 3:2:3, 1% → 0:2:5, 2% → 0:1:1, 2%) and
obtained as a beige solid (868 mg, 2.20 mmol, 65%). Single crystals suitable for X-ray diffraction
analysis were obtained from a hot saturated solution of the compound in ethyl acetate / n-hexane.
1H NMR (600.13 MHz, CDCl3, 295 K): δ (ppm) = 7.17 (s, 2 H), 5.97 (s, 2 H), 4.51 (dd, J = 9.7
Hz, J = 8.3 Hz, 2 H), 4.12 (t, J = 8.6 Hz, 2 H), 4.01-3.96 (m, 2 H), 2.53 (s, 6 H), 1.85-1.77 (m, 2
H), 1.09 (d, J = 6.7 Hz, 6 H), 0.95 (d, J = 6.7 Hz, 6 H). 13C{1H} NMR (150.90 MHz, CDCl3, 295
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K): δ (ppm) = 162.3, 157.9, 133.2, 132.1, 92.4, 72.6, 70.8, 33.2, 20.6, 19.6, 18.8. HRMS (ESI+):
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+
calcd. for C24H31N2O3 [M+H]+: 395.2329; found: 395.2333.
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Preparation of compound 7:
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Under ambient conditions, phthalic anhydride (7.39 g, 49.9 mmol, 1.0 eq.) and sodium sulfide
(16.8 g, 69.8 mmol, 1.4 eq.) nonahydrate were stirred at room temperature, which led to
liquefaction. After three days, the clear, orange liquid was quenched with 10% hydrochloric acid.
The resulting white solid was filtered, washed with water and dried by azeotropic distillation with
benzene. This product and ethyl 2-(triphenyl-λ5-phosphaneylidene)acetate (74.3 g, 213 mmol, 5
eq.) were suspended in 100 mL dry 1,4-dioxane and stirred overnight at 110 °C until NMR
analysis of the raw product showed complete conversion. The solvent was removed in vacuo and
the residue was purified by flash column chromatography (deactivated silica; petroleum
ether/ethyl acetate 3:1). The product was obtained as an orange-colored solid (2.82 g, 9.27 mmol,
19%). Single crystals suitable for X-ray diffraction analysis were obtained by layering a solution
1
of the compound in dichloromethane with n-pentane. H NMR (600.13 MHz, CDCl3, 295 K): δ
(ppm) = 7.79-7.78 (m, 2 H), 7.53-7.52 (m, 2 H), 6.63 (s, 2 H), 4.32 (q, 3J = 7.1 Hz, 4 H), 1.36 (t,
13
3J = 7.1 Hz, 6 H). C{1H} NMR (150.90 MHz, CDCl3, 295 K): δ (ppm) = 166.7, 155.8, 139.0,
130.9, 121.1, 107.2, 60.9, 14.6. HRMS (ESI+): calcd. for C16H16NaO4S+ [M+Na]+: 327.0662;
found: 327.0663.
Preparation of compound 16:
Under ambient conditions, diethyl ester 7 (2.16 g, 7.10 mmol, 1.0 eq.) was suspended in a
mixture of 100 mL ethanol, 30 mL tetrahydrofuran and 30 mL water. A solution of sodium
hydroxide (2.84 g, 71.0 mmol, 10 eq.) in 30 mL water was added and the mixture was stirred at
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room temperature for 3 hours. Subsequently, the organic solvents were removed in vacuo, the
residue dissolved in water and filtrated. The filtrate was acidified with 60 mL 10% hydrochloric
acid and stirred for 30 min. The resulting precipitate was filtered, washed with water and dried by
azeotropic distillation with benzene. The product was obtained as a yellow solid (1.39 g, 5.62
mmol, 79%). 1H NMR (600.13 MHz, DMSO-d6, 295 K): δ (ppm) = 12.76 (s, 2 H), 8.17-8.15 (m,
2 H), 7.62-7.60 (m, 2 H), 6.90 (s, 2 H). 13C{1H} NMR (150.90 MHz, DMSO-d6, 295 K): δ (ppm)
= 167.8, 155.1, 138.2, 131.2, 122.6, 108.2. HRMS (ESI–): calcd. for C12H7O4S– [M–H]–:
247.0071; found: 247.0069.
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Preparation of compound 18a:
Diacid 16 (750 mg, 3.02 mmol, 1.0 eq.) was suspended in 120 mL dry dichloromethane. In an ice
bath, a catalytic amount of N,N-dimethyl formamide and oxalyl chloride (1.50 mL, 2.22 g, 17.5
mmol, 5.8 eq.) were added dropwise. The suspension was allowed to warm up to room
temperature. After 20 h, all volatiles were removed in vacuo to yield a brown–green solid. This
crude dichloride was resuspended in 150 mL dry dichloromethane. (S)-2-Phenylglycinol (980
mg, 7.14 mmol, 2.4 eq.) and dry triethylamine (1.10 mL, 763 mg, 7.54 mmol, 2.5 eq.) were
dissolved in 5 mL dry dichloromethane and added dropwise at 0 °C. After 20 h, the reaction was
stopped by addition of water and stirred for 30 min. The resulting gum-like brown precipitate was
separated, washed with dichloromethane and water, dried by azeotropic distillation with benzene
and used without further purification. The product was obtained as a light brown solid (1.35 g,
1
3
2.77 mmol, 92%). H NMR (600.13 MHz, DMSO-d6, 295 K): δ (ppm) = 8.68 (d, J = 8.2 Hz, 2
H), 7.84-7.83 (m, H), 7.62-7.61 (m, 2 H), 7.36-7.31 (m, 8 H), 7.25-7.23 (m, 2 H), 7.02 (s, 2 H),
5.00-4.94 (m, 4 H), 3.64-3.61 (m, 4 H). 13C{1H} NMR (150.90 MHz, DMSO-d6, 295 K): δ (ppm)
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