Efficient Transfer of Chelating Amides into Different Types of Esters and Lactones

Article abstract of DOI:10.1002/ejoc.201402843

We describe a general and versatile approach for the conversion of carboxylic acid amides into their corresponding esters despite the fact that the former are thermodynamically more stable. The transformations are mediated by the coordination of Cu^I by a chelating entity. The resulting weakening of the amide bond allows for nucleophilic attack by alcoholic hydroxyl functions. The principle is demonstrated for a wide variety of transformations, leading to different kinds of esters and lactones. Due to their high resonance energy, amides are generally very stable towards solvolysis. However, bispicolylamides can be activated for alcoholysis by an unusual metal coordination involving the electron pair of the amide nitrogen. Herein, we widened the scope of the reaction by transforming the amides into a range of esters and lactones.

Full text of DOI:10.1002/ejoc.201402843

FULL PAPER
DOI: 10.1002/ejoc.201402843
Efficient Transfer of Chelating Amides into Different Types of Esters and
Lactones
Uwe Jakob,[a] Stephan Mundinger,[a] and Willi Bannwarth*[a]
Keywords: Synthetic methods / Amides / Esters / Protecting groups / Solvolysis / Lactones / Copper
We describe a general and versatile approach for the conver-
sion of carboxylic acid amides into their corresponding esters
despite the fact that the former are thermodynamically more
stable. The transformations are mediated by the coordination
of CuI by a chelating entity. The resulting weakening of the
amide bond allows for nucleophilic attack by alcoholic
hydroxyl functions. The principle is demonstrated for a wide
variety of transformations, leading to different kinds of esters
and lactones.
ive Cu(OTf)2, which had to be applied in equimolar
amounts. Hence, this could become an issue on a large-scale
synthesis. These disadvantages were solved by replacing bpa
with chelator amine 5, which we have named dmepa [N-
(dimethylaminoethyl)picolylamine]. Here, the methanolysis
of the pertinent amide with CuCl2 was far superior to that
with Cu(OTf)2 and was finished after less than one hour.[6]
Recently, we have extended the system with the tetradentate
amine 6 derived from N,NЈ-bis(picolyl)-N-propylethylenedi-
amine (bped, 6, Figure 1).
Introduction
In 1970, Houghton and Puttner published a seminal
work on chelating amides,[1] which served us as a basis for
the development of a new protection scheme for carboxylic
acids.[2] The approach is based on a mild conversion of a
carboxamide into a methyl ester by using Cu2+ salts in
methanol. The protection of carboxylic acids with bispicol-
ylamine (bpa) as chelating entity fulfilled almost all criteria
for an ideal protecting group for carboxylic acids. The pro-
tection was easily performed starting from the carboxylic
acid and bispicolylamine by applying a commonly used ac-
tivating agent such as N,N,NЈ,NЈ-tetramethyl-O-(benzotri-
azol-1-yl)uronium tetrafluoroborate (TBTU).[3] The re-
sulting amide 1 turned out to be very robust and could be
applied in combination with a wide variety of reaction con-
ditions. Moreover, the transformation into its methyl ester
or the free acid is possible under mild reaction conditions
involving the amide nitrogen in an unusual complexation to
Cu2+ as in 2. The involvement of the amide nitrogen in
the complexation to Cu2+ leads to an enhancement of the
electrophilicity on the carbonyl C-atom, rendering it
amenable for a nucleophilic attack by MeOH.[4] The trans-
formation into the free acid was achieved in the presence
of Ba(OH)2·8H2O followed by acidic workup (Scheme 1).
Attempts to achieve the direct transfer of 2 into the free
acid in aqueous systems was unsuccessful. We had demon-
strated the principle for aromatic and aliphatic acids as well
as for amino acids.[5] The only disadvantages of the initially
reported bpa-based relay protection scheme were the rela-
tively long reaction times and the use of the rather expens-
Scheme 1. Principle of the solvolysis reaction of bpa-derived
amides.
Figure 1. Structures of chelating amines 5 (dmepa) and 6 (bped).
Surprisingly, methanolysis of the corresponding amides
of amine 6 was fastest with Zn(OTf)2. From the rate of
methanolysis with different salts, we surmised that even an
orthogonal hydrolysis of amides carrying either bpa, 5 or 6
should be feasible. To verify this assumption, we synthe-
sised a trisamide that incorporated the three different chela-
[a] Institut für Organische Chemie, Albert-Ludwigs-Universität
Freiburg,
Albertstr. 21, 79104 Freiburg, Germany
E-mail: willi.bannwarth@organik.chemie.uni-freiburg.de
http://www.chemie.uni-freiburg.de/orgbio/w3bann/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402843.
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tors embedded into the same chemical environment so that
differences in the rate of methanolysis could be directly at-
tributed to the individual chelating protecting group.
Methanolysis reactions using first FeCl3, then Zn(OTf)2
and then CuCl2 yielded finally the desired tris methyl ester.
The individual cleavage processes occurred with complete
selectivity.[6] All activities concerning chelating amides pub-
lished so far have focused on methanolysis reactions em-
ploying MeOH as a nucleophile. In the present work we
aimed to establish a general method for the transformation
of chelating amides into esters. Such an approach could be
regarded as a change of paradigm in synthetic organic
chemistry. Due to the higher thermodynamic stability of
amides with respect to esters, which is in the order of 30 kJ/
mol, this transformation is generally only possible the other
way round.
As a consequence, nonenzymatic solvolytic reactions of
carboxamides are only possible if special criteria are met
that lead to a pyramidalisation of the nitrogen, thereby pre-
venting amide resonance and simultaneously enhancing the
electrophilicity on the carbon, rendering it susceptible to
nucleophilic attack. This leads to a concomitant increase of
the basicity of the nitrogen. Prominent examples for such
twisted amides (Figure 2) revealing these properties are il-
lustrated by structures 7–9,[7] as well as by the medium-
bridged lactams of basic type 10.[8] Furthermore, the amide
resonance can also be prevented in sterically demanding
amides such as in 11[9] or in amides in which a combination
of steric demand together with an electron-withdrawing
substituent on the α-carbon as in 12 can be applied. For the
last example, an interesting mechanism involving a ketene
intermediate has been postulated.[10] The transfer of amides
into esters can also be facilitated, if a byproduct can be
trapped to form a thermodynamic sink that compensates
for the difference in thermodynamic stability between
amides and esters and even rendering the reaction irrevers-
ible. Such an approach was recently demonstrated for the
transformation of amides of type 13 into nBu esters 14, with
the initially formed amino ethanol being trapped as oxazol-
idinone 15 (Scheme 2). The reaction is also entropically fa-
voured.[11]
Scheme 2. Transfer of amide 13 into n-butyl ester 14 with concomi-
tant transfer of aminoethanol into cyclic urethane 15.
plied, for example, to the synthesis of natural products. As
mentioned earlier, the advantage of using chelating amides
as relay protecting groups is the mild cleavage conditions;
this is achieved through complexation to a metal ion with
the unusual involvement of the free electron pair of the
amide nitrogen followed by nucleophilic attack of meth-
anol.[12] In contrast to the structurally fixed examples of
twisted amides shown in Figure 2, we induced the reaction
by complexation, and the resulting pyramidalisation is then
the prerequisite for the methanolysis, which proceeds poss-
ibly by a methoxide as nucleophile.[4] In addition, the cleav-
age process yields bpa-metal complex, which is thermody-
namically more stable than amide complex 2. For these
reasons, these amide systems represent a combination of the
pyramidalisation of the nitrogen together with a thermody-
namically relevant stable side product. Prior to this work,
we had applied these favourable properties for the develop-
ment of linker systems for solid-phase chemistry.[13] Taking
all aspects together, we surmised that our systems might be
generally prone to a transformation into esters or might
even have the potential to transform amide-protected
hydroxy carboxylic acids into lactones. With respect to the
chelating protection scheme, such a technique would signifi-
cantly widen the scope of application. This would allow
amides to be transferred after synthetic operations into dif-
ferent kinds of esters, which would allow for specific or-
thogonal deprotections or further manipulations such as
allyl esters in Tsuji–Trost reactions.[14] As a further option,
the still protected amide could possibly be transformed di-
rectly into lactones.
Results and Discussion
The rates of methanolysis of the bpa-amide of benzoic
acid 1a (R = C6H5) after the application of Cu(OTf)2,
CuCl2, CuCl, Cu(OAc)2 and FeCl3 are depicted in Figure 3.
As can be deduced from the plots, the rate of transforma-
tion into methyl ester 16a increased in the order: CuCl2 Ͻ
Cu(OTf)2 Ͻ FeCl3 Ͻ Cu(OAc)2 Ͻ CuCl, with the last being
far superior as activating agent. When switching to EtOH
as nucleophile and using the same metal salts for activation,
the formation of the corresponding ethyl ester 20a dropped
significantly when CuCl2, Cu(OTf)2, Cu(OAc)2 or FeCl3
were employed. In contrast, we realised to our delight that
CuCl still mediated a fast, efficient and mild transfer to the
Figure 2. Reactive amides.
Unfortunately, as far as the synthetic utility of twisted or ethyl ester 17a in less than 2 h at room temp. The reason
nonplanar amides is concerned, only the bridged medium- for this unexpected behaviour of CuCl is a topic of ongoing
sized lactams of type 10 might have the potential to be ap- research (Figure 4).
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Transfer of Chelating Amides into Esters and Lactones
Figure 4. Rate of ethanolysis for amide 1a using various metal salts.
Figure 3. Rate of methanolysis for amide 1a using various metal
salts.
experiments prompted us to test amide 1a with an array
of different alcohols, leading to esters 18a–25a (Scheme 3).
Despite the fact that CuCl is only poorly soluble in the Thus, we dissolved amide 1a in a 1:1 mixture of MeCN and
applied mixture of MeCN and EtOH, the rate of transfor- the alcohol, then solid CuCl was added and the progress of
mation was nevertheless highly dependent on the stoichio- the reaction was followed by HPLC. As illustrated in Fig-
metry, which might be due to an enhanced surface area. ure 5, most reactions were complete after approximately 1 h
For this reason, we carried out all the following experiments at room temp. Slightly longer reaction times were required
with 5 equiv. CuCl. The intriguing results in the ethanolysis for the formation of esters 22a and 23a.
Scheme 3. Array of esters 18a,b–25a,b obtained from the bpa-derived amide 1a (aromatic) and 1b (aliphatic).
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approximately 50 °C, which led then to a conversion of ap-
proximately 80%.
In the experiments outlined above, the alcoholysis reac-
tions were carried out with a relatively large excess of the
alcohol. Nevertheless, the results encouraged us to investi-
gate the possibility of synthesising lactones in an intramo-
lecular manner. For this purpose, hydroxy amide 26b, which
had been prepared through coupling of benzoyl propionic
acid with bpa followed by reduction with NaBH4, was used
as a benchmark substrate to establish optimal conditions
especially concerning the use of metal salts. The formation
of the pertinent phenyl lactone 26c was monitored by
HPLC. It turned out that 26b could be successfully trans-
formed into the phenyl lactone 26c by using CuCl2
(1.1 equiv.), CuICl (5 equiv.) or Cu(OAc)2 (1.1 equiv.) in
MeCN in high yields, and the reaction was already com-
plete after 1 h. In contrast, the presence of Cu(OTf)2 and
Zn(OTf)2 led to slow formation of the lactone (Ͻ 5% after
6 h) but the reaction rate could be significantly enhanced
by adding DIPEA (1.1 equiv.; Figure 7). In summary, the
use of CuICl turned out to be superior compared with the
use of other metal salts. For this reason substrates 26b–34b
were also transformed into their corresponding γ-, δ- and
ε-lactones by using 5 equiv. CuICl. The products were iso-
lated after short column chromatography on a preparative
scale and in decent yields (Table 1). The formation of me-
dium-sized lactones was not successful and we were not
able to prepare macro lactones. Corresponding dmepa- and
bped-analogues had also been successfully synthesised and
transformed into lactones but because the results obtained
with the bpa derivatives were more convincing, the dmepa-
and bped-conversions were not elaborated in more detail.
Figure 5. Transformation of bpa-derivative 1a into esters 18a–25a
by using a range of alcohols.
The same positive result was obtained with phenol (24a)
as nucleophile. With 2-propanol as sterically more de-
manding secondary alcohol, the transformation into iso-
propyl ester 25a at room temp. was relatively slow but could
be improved significantly by elevating the reaction tempera-
ture to 50 °C and/or by adding DIPEA so that it was also
complete after approximately 3 h. Recently, we were able to
demonstrate that the approach is not restricted to aromatic
amides and that we also observed the formation of methyl
esters when aliphatic amides were used.[5,6] To demonstrate
that it is possible to synthesise various esters from aliphatic
amides, we prepared esters 18b–25b by applying a range of
alcohols. The quantitative transformation of aliphatic
amide 1b into esters 18b–25b required only slightly longer
reaction times (Figure 6). In most cases, we obtained the
esters in a quantitative manner when the reaction was con-
ducted at room temp. Only in the case of methylthioethanol
was the reaction carried out at an elevated temperature of
Figure 6. Transformation of bpa-derivative 1b into esters 18b–25b
by using various alcohols.
Figure 7. Transformation of hydroxy amide 26b into lactone 26c
under various reaction conditions.
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Transfer of Chelating Amides into Esters and Lactones
Table 1. Array of different lactones 26c–34c synthesised from hy-
droxy-amide precursors 26b–34b.
Conclusions
We have described a synthetically useful approach for the
transformation of carboxamides into the corresponding es-
ters. The unusual principle enables for this transfer to take
place under very mild conditions despite of the fact that
carboxamides are thermodynamically more stable than the
resulting esters. This reaction can otherwise only be medi-
ated by enzymes. The principle was demonstrated for bpa-
derived chelating amides, which are prone to undergo nucle-
ophilic attack by hydroxy functions after addition of CuICl,
leading to esters or lactones, respectively. The results should
be of high value in synthetic organic chemistry.
Experimental Section
General: 1H NMR spectra were recorded with a Bruker AM 400
(400 MHz) or a Varian Mercury VX 300 (300 MHz) spectrometer
as solutions in CDCl3, [D4]MeOH or [D6]DMSO. Chemical shifts
are expressed in parts per million (ppm, δ) downfield from
tetramethylsilane (TMS, δ = 0 ppm) and are referenced to CHCl3
(δ = 7.26 ppm), MeOH (δ = 3.31 ppm) or DMSO (δ = 2.50 ppm)
as internal standard. All coupling constants are absolute values and
J values are expressed in Hertz [Hz]. The description of signals
include: s = singlet, br. s = broad singlet, d = doublet, t = triplets,
m = multiplet, mc = centred mutiplet, dd = doublet of doublets,
ddd = doublet of doublet of doublets, dddd = doublet of doublet
of doublet of doublets, dt = doublet of triplets, td = triplet of doub-
let. The spectra were analysed according to first order. 13C NMR
spectra were recorded with a Bruker AM 400 (100 MHz) or a
Bruker Avance DRX (125 MHz) spectrometer as solutions in
CDCl3, MeOH or DMSO. Chemical shifts are expressed in parts
per million (ppm, δ) downfield from tetramethylsilane (TMS, δ =
0 ppm) and are referenced to CHCl3 (δ = 77.0 ppm), MeOH (δ =
49.0 ppm) or DMSO (δ =39.5 ppm) as internal standard. MS (EI,
electron impact mass spectrometry), MS (CI, chemical ionization
mass spectrometry) and GC/MS (EI or CI) were recorded with an
TSQ 700 spectrometer. MS (ESI, electrospray ionisation mass spec-
trometry) or MS (APCI, atmospheric pressure chemical ionisation
mass spectrometry) were measured with an LCQ Advantage or Ex-
active. HRMS spectra were recorded with a Thermo Exactive with
Orbitrap-Analysator spectrometer. The molecular fragments are
quoted as the relation between mass and charge (m/z), the inten-
sities as a percentage value relative to the intensity of the base sig-
nal (100%). The molecular ion contains the abbreviation [M+]. An-
alytical thin-layer chromatography (TLC) was carried out on
Merck silica gel coated aluminium plates (silica gel 60, F254), de-
tected under UV-light at 254 nm. Solvent mixtures are understood
as volume/volume. Solvents, reagents and chemicals were pur-
chased from Acros, ABCR, Alfa Aesar, Merck or Sigma–Aldrich.
Dichloromethane (CH2Cl2) was distilled from calcium hydride
prior to use. Anhydrous toluene and THF were distilled from so-
dium using benzophenone as indicator in case of THF. All other
solvents, reagents and chemicals were used as purchased. All reac-
tions involving moisture-sensitive reactants were executed under an
argon atmosphere, using oven-dried and/or flame-dried glassware.
Purification by column chromatography was performed by using
freshly distilled solvents CH2Cl2, cyclohexane (CH), EtOAc (EE)
and MeOH (p.A. quality). The solid phase consisted of either silica
gel (Kieselgel 60, Fa. Merck, size 40–63 μm) or basic aluminium
oxide (activity 1, Fa. Machery–Nagel). HPLC-measurements were
performed with an Agilent 1100 Series and column from Waters
[a] CuCl (5 equiv.), MeCN, room temp., 6 h. [b] Isolated yield after
column chromatography.
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(μBondapak C18; 3.9 mmϫ150 mm). Samples for the HPLC mea-
surements were taken with Hamilton syringes (Terumo Micro Sy-
ringe MS50 and Hamilton GASTIGHT 250 μL). The mobile phase
was mixtures of MeCN/H2O. Phenol was used as internal standard.
Bispicolyl Amide γ-tert-Butyl Z-
L
-Glutamate (1b): Z-Glu(OtBu)-
OH was converted into the pertinent bispicolyl amide 1b according
to General Procedure A. After purification by column chromatog-
raphy (silica gel; CH2Cl2 ǞCH2Cl2/MeOH, 96:4), amide 1b (0.89 g,
1.72 mmol, 87%) was obtained as a pale-yellow gum. 1H NMR
(300 MHz, CDCl3): δ = 1.40 [s, 9 H, C(CH3)3], 2.09–2.19 (m, 2 H,
CH2CH2), 2.27 (mc, 2 H, CH2CH2), 4.60 (m, 1 H, α-CH), 4.78–
4.91 (m, 4 H, 2ϫCH2Py), 5.03–5.11 (m, 2 H, CH2Ph), 5.70 (d, J
= 8.7 Hz, 1 H, NHCO2), 7.12–7.38 (m, 9 H, ArH), 7.58 (dt, J =
11.5, 1.9 Hz, 1 H, ArH), 7.59–7.65 (m, 1 H, ArH), 8.48 (ddd, J =
4.9, 1.8, 0.9 Hz, 1 H, ArH), 8.52–8.53 (m, 1 H, ArH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 28.2, 28.7, 29.4, 29.5, 31.2, 38.7,
50.8, 51.4, 52.8, 66.9, 80.7, 121.8, 122.4, 122.5, 122.8, 128.1, 128.2,
128.6, 136.6, 136.9, 149.4, 149.9, 156.1, 157.0, 172.4, 172.9 ppm.
MS (+ APCI): m/z (%) = 519.3 (100) [M + H]+. HRMS (+ APCI,
MeOH): m/z calcd. for C29H35N4O5 [M + H]+ 519.26075; found
519.26000.
Acylation with TBTU and the Carboxylic Acid; General Procedure
A: The carboxylic acid (1.0 equiv. or 1.4 equiv.) and TBTU
(1.0 equiv. or 1.4 equiv.) were suspended in CH2Cl2 and N,N-diiso-
propylethylamine (DIPEA; 6.0 equiv.) was added. After 10 min, the
secondary amine (1.0 equiv.) was added. After stirring overnight at
room temp., the mixture was washed with water (2 times) and dried
with Na2SO4. The organic solvent was removed under reduced
pressure and the crude product was purified by flash chromatog-
raphy (silica gel; CH2Cl2/MeOH, 98:2Ǟ85:15 or aluminium oxide
with CH/EE mixtures).
Esterification with DCC; General Procedure B: The carboxylic acid
(1.0 equiv.)
and
4-(N,N-dimethylamino)pyridine
(DMAP;
0.1 equiv.) were dissolved in CH2Cl2 and ROH (3.0 equiv.). After
30 min stirring at room temp., the reaction was cooled to 0 °C and
N,NЈ-dicyclohexylcarbodiimide (DCC; 1.0 equiv.) was added in one
portion. After stirring at room temp. overnight, urea was filtered
off using a kieselguhr plug. The organic solvent was removed under
reduced pressure and the crude product was purified by flash
chromatography (silica gel; CH2Cl2).
Methyl Benzoate (16a):[15] Synthesised according to General Pro-
cedure B. Purification by column chromatography (silica gel,
CH2Cl2) gave 16a (0.52 g, 3.82 mmol, 95%) as a colourless liquid.
1H NMR (400 MHz, CDCl3): δ = 3.91 (s, 3 H, OCH3), 7.40–7.45
(m, 2 H, ArH), 7.52–7.56 (m, 1 H, ArH), 8.02–8.05 (m, 2 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 52.1, 128.3, 129.6,
130.2, 132.9, 167.1 ppm. MS (GC/MS-EI): m/z (%) = 105.1 (100)
[M – OCH3]+, 136.1 (53) [M+]. HRMS (+ APCI, MeOH): m/z
calcd. for C8H9O2 [M + H]+ 137.06025; found 137.06020.
Reduction of Keto Functions in Keto Amides; General Procedure C:
The keto amide was solved in a mixture of MeOH/Et2O (1:1 ratio;
p.A. grade). NaBH4 (2.0 equiv.) was dissolved in a little water and
added to the keto amide derivative. The whole reaction mixture was
stirred at room temperature overnight. A half-saturated solution of
NaHCO3 was then added and the aqueous phase was extracted
three times with CH2Cl2. The combined organic phases were dried
with Na2SO4 and the solvent was removed under reduced pressure.
The hydroxy amides 26b–34b were isolated after column
chromatography (silica gel; CH2Cl2 ǞCH2Cl2/MeOH, 90:10).
5-tert-Butyl 1-Methyl 2-{[(Benzyloxy)carbonyl]amino}pentanedioate
(16b):[16] Synthesised according to the General Procedure B. Purifi-
cation by column chromatography (silica gel; CH2Cl2/MeOH, 98:2)
gave 16b (0.47 g, 1.34 mmol, 97%) as a colourless liquid. 1H NMR
(400 MHz, CDCl3): δ = 1.43 [s, 9 H, C(CH3)3], 1.95 (mc, 1 H,
NHCHCHCH2), 2.09–2.20 (m, 1 H, NHCHCHCH2), 2.21–2.39
(m, 2 H, CH2COOtBu), 3.74 (s, 3 H, OCH3), 4.39 (mc, 1 H,
NHCH), 5.10 (s, 2 H, CH2Ph), 5.42 (mc, 1 H, NH), 7.28–7.38 (m,
5 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.7, 28.1, 31.5,
52.5, 53.6, 67.1, 80.9, 128.1, 128.2, 128.6, 136.3, 156.0, 172.0,
172.5 ppm. MS (+ ESI): m/z (%) = 374.2 (100) [M + Na]+. HRMS
(+ ESI, MeOH): m/z calcd. for C18H25NO6Na [M + Na]+
374.15796; found 374.15790.
Esterification Using CuICl; General Procedure D: Amide 1a/b was
solved in a mixture of MeCN and the pertinent alcohol [1:1 ratio
(v/v); exception: phenol, 10 equiv. for 1a, 40 equiv. for 1b] and solid
CuICl (5 equiv.) was added. The resulting suspension was stirred
and the progress of the reaction was monitored by HPLC (UV
detection at 254 nm for aromatic esters 16a–25a; detection at
210 nm for aliphatic esters 16b–25b; independently synthesised es-
ters were used to obtain calibration lines).
Ethyl Benzoate (17a):[17] Synthesised according to the General Pro-
cedure B. Purification by column chromatography (silica gel;
CH2Cl2) gave 17a (0.56 g, 3.73 mmol, 90%) as a colourless liquid.
1H NMR (400 MHz, CDCl3): δ = 1.39 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 4.37 (q, J = 7.1 Hz, 2 H, OCH2CH3), 7.40–7.45 (m, 2
H, ArH), 7.51–7.56 (m, 1 H, ArH), 8.03–8.06 (m, 2 H, ArH) ppm.
13C NMR (100 MHz, CDCl3): δ = 14.3, 60.9, 128.3, 129.6, 130.6,
132.8, 166.6 ppm. MS (+ APCI): m/z (%) = 151.0 (100) [M + H]+.
HRMS (+ APCI, MeOH): m/z calcd. for C9H11O2 [M + H]+
151.07590; found 151.07600.
Lactonisation Using CuICl in MeCN; General Procedure E: A
10 mm solution of the hydroxy amide 26b–34b in MeCN was stirred
for 5 min. Solid CuICl was then added in one portion and the sus-
pension was stirred for 6 h at room temp. After removing a large
part of the solvent, the residue was purified by filtration through a
small layer of silica gel using CH2Cl2 as eluent. Evaporation of the
solvent gave lactones 26c–34c (for yields, see Table 1).
Benz-bis[(2-pyridyl)methyl]amine (1a): Synthesised according to Ge-
neral Procedure A. The resulting dark oil was purified by column
chromatography (silica gel; CH2Cl2/MeOH, 98:2Ǟ95:5). The re-
sulting yellow gum (0.97 g, 3.20 mmol, 80%) crystallised overnight,
m.p. 58–59 °C. 1H NMR (400 MHz, CDCl3): δ = 4.70 (s, 2 H,
CH2Py), 4.90 (s, 2 H, CH2Py), 7.19 (m, 3 H, ArH), 7.32–7.45 (m,
5-tert-Butyl 1-Ethyl 2-{[(Benzyloxy)carbonyl]amino}pentanedioate
(17b):[18] Synthesised according to General Procedure B. Purifica-
tion by column chromatography (silica gel; CH2Cl2/MeOH, 98:2)
gave 17b (0.47 g, 1.29 mmol, 93%) as a colourless liquid. 1H NMR
(400 MHz, CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3 H, CH2CH3), 1.43
4 H, ArH), 7.52–7.56 (m, 2 H, ArH), 7.62–7.72 (m, 2 H, ArH), [s, 9 H, C(CH3)3], 1.94 (mc, 1 H, NHCHCHCH2), 2.09–2.20 (m, 1
8.50–8.59 (m, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = H, NHCHCHCH2), 2.23–2.39 (m, 2 H, CH2COOtBu), 4.19 (q, J
50.5, 54.6, 121.4, 122.4, 122.5, 127.0, 128.5, 129.8, 136.0, 136.8,
= 7.1 Hz, 2 H, CH2CH3), 4.36 (mc, 1 H, NHCH), 5.10 (s, 2 H,
149.4, 149.9, 156.8, 157.2, 172.6 ppm. MS (CI, NH3): m/z (%) = CH2Ph), 5.39 (mc, 1 H, NH), 7.27–7.36 (m, 5 H, ArH) ppm. 13C
304.1 (100) [M + H]+. HRMS (CI, NH3): m/z calcd. for C19H17N3O
[M + H]+ 304.13716; found 304.13720. C19H17N3O (303.36): calcd.
C 75.23, H 5.65, N 13.85; found C 75.06, H 5.62, N 13.81.
NMR (100 MHz, CDCl3): δ = 14.2, 27.8, 28.1, 31.5, 53.6, 61.6,
67.1, 80.8, 128.1, 128.2, 128.6, 136.4, 156.0, 172.0 ppm. MS (+
ESI): m/z (%) = 388.2 (100) [M + Na]+. HRMS (+ ESI, MeOH):
6968
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6963–6974

Transfer of Chelating Amides into Esters and Lactones
m/z calcd. for C19H27NO6Na [M + Na]+ 388.17361; found
388.17330.
MeOH): m/z calcd. for C14H16NO2 [M + NH4]+ 230.11810; found
230.11820. C14H12O2 (212.25): calcd. C 79.23, H 5.70; found C
78.70, H 5.80.
2,2,2-Trichloroethyl Benzoate (18a):[19] Synthesised according to
General Procedure B. Purification by column chromatography (sil-
ica gel; CH2Cl2) gave 18a (0.79 g, 3.12 mmol, 76%) as a colourless
1-Benzyl 5-tert-Butyl 2-{[(Benzyloxy)carbonyl]amino}pentanedioate
(20b):[20] Synthesised according to General Procedure B. Purifica-
tion by column chromatography (silica gel; CH2Cl2/MeOH, 98:2)
gave 20b (0.52 g, 1.22 mmol, 87%) as a colourless liquid. 1H NMR
(400 MHz, CDCl3): δ = 1.42 [s, 9 H, C(CH3)3], 1.87–2.05 (m, 1 H,
NHCHCHCH2), 2.06–2.21 (m, 1 H, NHCHCHCH2), 2.22–2.40
(m, 2 H, CH2COOtBu), 4.44 (mc, 1 H, NHCH), 5.10 (s, 2 H,
NHCOOCH2Ph), 5.17 (s, 2 H, CHCOOCH2Ph), 5.43 (mc, 1 H,
NH), 7.27–7.41 (m, 10 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 27.6, 28.1, 31.4, 53.6, 67.1, 67.3, 80.9, 128.2, 128.3,
128.5, 128.6, 128.7, 135.3, 136.2, 140.5, 156.0, 171.9, 172.0 ppm.
MS (+ APCI): m/z (%) = 428.2 (100) [M + H]+. MS (– APCI): m/z
(%) = 462.2 (100) [M + Cl]–. HRMS (+ APCI, MeOH): m/z calcd.
for C24H30NO6 [M + H]+ 428.20731; found 428.20730. HRMS
(– APCI, MeOH): m/z calcd. for C24H29NO6Cl [M + Cl]–
462.16834; found 462.16860. HRMS (– APCI, MeOH) m/z [(M –
H)–]: Calcd. for C24H28NO6: 426.19166, found 426.19190.
1
liquid. H NMR (400 MHz, CDCl3): δ = 4.97 (s, 2 H, CH2), 7.46–
7.52 (m, 2 H, ArH), 7.60–7.65 (m, 1 H, ArH), 8.12–8.16 (m, 2 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 74.5, 76.4, 95.1,
128.7, 128.8, 130.1, 133.9 ppm. MS (GC/MS-CI, NH3): m/z (%) =
105.1 (100) [M – OCH2CCl3]+, 254.0 (20) [M + H]+. C9H7Cl3O2
(253.51): calcd. C 42.64, H 2.78; found C 42.46, H 2.73.
5-tert-Butyl
1-(2,2,2-Trichloroethyl)
2-{[(Benzyloxy)carbonyl]-
amino}pentanedioate (18b): Synthesised according to General Pro-
cedure B. Purification by column chromatography (silica gel;
CH2Cl2/MeOH, 98:2) gave 18b (0.57 g, 1.22 mmol, 88%) as a
colourless liquid. 1H NMR (400 MHz, CDCl3): δ = 1.43 [s, 9 H,
C(CH3)3], 1.94–2.11 (m, 1 H, NHCHCHCH2), 2.16–2.32 (m, 1 H,
NHCHCHCH2), 2.33–2.46 (m, 2 H, CH2COOtBu), 4.52 (mc, 1 H,
NHCH), 4.67 (d, J = 11.8 Hz, 1 H, OCHCCl3), 4.90 (d, J =
11.8 Hz, 1 H, OCHCCl3), 5.11 (s, 2 H, CH2Ph), 5.49 (mc, 1 H,
NH), 7.27–7.39 (m, 5 H, ArH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 27.1, 28.1, 31.5, 53.7, 67.3, 74.4, 81.1, 94.5, 128.2, 128.3, 128.6,
136.2, 156.1, 170.7, 172.0 ppm. MS (+ APCI): m/z (%) = 468.1
(100) [M + H]+. MS (– APCI): m/z (%) = 504.0 (100) [M + Cl]–.
HRMS (+ APCI, MeOH): m/z calcd. for C19H25NO6Cl3 [M +
H]+ 468.07475; found 468.07480. HRMS (– APCI, MeOH): m/z
calcd. for C19H24NO6Cl4 [M + Cl]– 502.03577; found 502.03620.
2-(tert-Butoxycarbonylamino)-2-(methoxycarbonylethyl) Benzoate
(21a): Synthesised according to General Procedure B. Purification
by column chromatography (silica gel; CH2Cl2) gave 21a (0.50 g,
1.55 mmol, 38%) as a white solid, m.p. 130–132 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.44 [s, 9 H, C(CH3)3], 3.80 (s, 3 H, OCH3),
4.56–4.68 (m, 2 H, OCH2CH), 4.69–5.46 (m, 1 H, OCH2CH), 7.40–
7.48 (m, 2 H, ArH), 7.58–7.60 (m, 1 H, ArH), 7.97–8.03 (m, 2 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 26.9, 28.3, 34.0,
52.9, 53.1, 65.0, 80.5, 128.5, 129.5, 129.8, 133.4, 155.2, 166.1,
170.4 ppm. MS (+ APCI): m/z (%) = 341.1 (100) [M + NH4]+.
HRMS (+ APCI, MeOH/NH4+): m/z calcd. for C16H25N2O6 [M +
NH4]+ 341.17126; found 341.17110. C16H21NO6 (323.35): calcd. C
59.43, H 6.55, N 4.33; found C 58.96, H 6.67, N 4.20.
Allyl Benzoate (19a):[19] Synthesised according to General Pro-
cedure B. Purification by column chromatography (silica gel;
CH2Cl2) gave 19a (0.60 g, 3.70 mmol, 90%) as a colourless liquid.
1H NMR (400 MHz, CDCl3):
δ = 4.81–4.84 (m, 2 H,
OCH2CHCH2), 5.26–5.44 (m, 2 H, OCH2CHCH2), 5.99–6.09 (m,
1 H, OCH2CHCH2), 7.41–7.46 (m, 2 H, ArH), 7.52–7.57 (m, 1 H,
ArH), 8.05–8.08 (m, 2 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 65.5, 118.2, 128.4, 129.7, 130.2, 132.2, 133.0,
166.3 ppm. MS (GC/MS-EI): m/z (%) = 105.1 (100) [M – O-allyl]+,
162.1 (14) [M+]. HRMS (+ APCI, MeOH): m/z calcd. for C10H11O2
[M + H]+ 163.07590; found 163.07610.
1-[2-(tert-Butoxycarbonylamino)-3-methoxy-3-oxopropyl]
5-tert-
Butyl 2-[(Benzyloxycarbonyl)amino]pentanedioate (21b): Synthe-
sised according to General Procedure B. Purification by column
chromatography (silica gel; CH2Cl2/MeOH, 98:2) gave 21b (0.57 g,
1.06 mmol, 76%) as a colourless liquid. 1H NMR (400 MHz,
CDCl3): δ = 1.43 [s, 9 H, C(CH3)3], 1.45 [s, 9 H, NHCOOC(CH3)3],
5-tert-Butyl
1-Prop-2-en-1-yl
2-{[(Benzyloxy)carbonyl]amino}-
pentanedioate (19b): Synthesised according to general procedure B.
1.88–2.07 (m,
1 H, NHCHCHCH2), 2.07–2.23 (m, 1 H,
Purification by column chromatography (silica gel; CH2Cl2/MeOH,
NHCHCHCH2), 2.25–2.40 (m, 2 H, CH2COOtBu), 3.76 (s, 3 H,
OCH3), 4.28–4.45 (m, 2 H, NHCH, NHCH), 4.45–4.62 (m, 2 H,
NHCHCH2OOCCH), 5.11 (mc, 2 H, CH2Ph), 5.45 (mc, 1 H,
NHCHCH2CH2), 5.56 (m, 1 H, NHCHCH2O), 7.27–7.40 (m, 5 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.2, 28.1, 28.4,
31.3, 52.9, 53.7, 65.2, 67.2, 80.5, 81.2, 128.2, 128.3, 128.6, 136.2,
140.5, 155.4, 156.0, 170.0, 171.5, 172.1 ppm. MS (+ APCI): m/z
(%) = 539.3 (100) [M + H]+. MS (– APCI): m/z (%) = 573.2 (100)
[M + Cl]–. HRMS (+ APCI, MeOH): m/z calcd. for C26H39N2O10
[M + H]+ 539.26047; found 539.26040. HRMS (– APCI, MeOH):
1
98:2) gave 19b (0.51 g, 1.35 mmol, 97%) as a colourless liquid. H
NMR (400 MHz, CDCl3): δ = 1.42 [s, 9 H, C(CH3)3], 1.95 (mc, 1
H, NHCHCHCH2), 2.09–2.22 (m, 1 H, NHCHCHCH2), 2.23–2.40
(m, 2 H, CH2COOtBu), 4.41 (mc, 1 H, NHCH), 4.63 (d, J = 5.4 Hz,
2 H, OCH2CHCH2), 5.10 (s, 2 H, CH2Ph), 5.25 (dd, J = 10.4,
1.1 Hz, 1 H, OCH2CHCH), 5.32 (dd, J = 10.4, 1.1 Hz, 1 H,
OCH2CHCH), 5.41 (mc,
OCH2CHCH2), 7.27–7.37 (m,
1
H, NH), 5.83–5.95 (m,
5
1 H,
H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 27.8, 28.2, 31.6, 53.7, 66.2, 67.2, 80.9,
119.1, 128.2, 128.3, 128.6, 131.6, 136.4, 156.1, 171.8, 172.1 ppm.
MS (+ ESI): m/z (%) = 400.2 (100) [M + Na]+. HRMS (+ ESI,
MeOH): m/z calcd. for C20H27NO6Na [M + Na]+ 400.17361; found
400.17350.
m/z calcd. for C26H38N2O10Cl [M
+
Cl]– 573.22150; found
573.22150.
2-Methylsulfanylethyl Benzoate (22a): Synthesised according to Ge-
neral Procedure B. Purification by column chromatography (silica
gel; CH2Cl2) gave 22a (0.79 g, 4.03 mmol, 90%) as a colourless li-
Benzyl Benzoate (20a):[19] Synthesised according to General Pro-
cedure B. Purification by column chromatography (silica gel;
CH2Cl2) gave 20a (0.71 g, 3.35 mmol, 82%) as a colourless liquid.
1
quid. H NMR (400 MHz, CDCl3): δ = 2.20 (s, 3 H, SCH3), 2.86
1H NMR (400 MHz, CDCl3): δ = 5.37 (s, 2 H, CH2), 7.31–7.47 (m, (t, J = 6.8 Hz, 2 H, CH2SCH3), 4.49 (t, J = 6.8 Hz, 2 H,
7 H, ArH), 7.52–7.57 (m, 1 H, ArH), 8.06–8.10 (m, 2 H, ArH) ppm.
13C NMR (100 MHz, CDCl3): δ = 24.7, 25.5, 35.0, 55.8, 66.7, ArH), 8.03–8.07 (m, 2 H, ArH) ppm. 13C NMR (100 MHz,
128.2, 128.3, 128.4, 128.6, 129.8, 130.2, 133.1, 136.1 ppm. MS (+ CDCl3): δ = 15.9, 32.7, 63.6, 128.4, 129.6, 130.1, 133.1, 166.4 ppm.
APCI): m/z (%) = 230.1 (100) [M + NH4]+. HRMS (+ APCI, MS (GC/MS-CI, NH3): m/z (%) = 214.2 (100) [M + NH4]+, 197.1
CH2CH2SCH3), 7.41–7.46 (m, 2 H, ArH), 7.53–7.58 (m, 1 H,
Eur. J. Org. Chem. 2014, 6963–6974
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6969

W. Bannwarth et al.
FULL PAPER
(67) [M + H]+. C10H12O2S (196.26): calcd. C 61.20, H 6.16, S 16.34;
found C 61.24, H 6.12, S 16.18.
1 H, ArH), 7.29–7.41 (m, 7 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 27.6, 28.1, 31.6, 53.9, 67.2, 77.3, 81.1, 121.4, 126.2,
128.2, 128.3, 128.6, 129.6, 136.3, 150.5, 156.1, 170.8, 172.0 ppm.
MS (+ ESI): m/z (%) = 436.2 (100) [M + Na]+. HRMS (+ ESI,
MeOH): m/z calcd. for C23H27NO6Na [M + Na]+ 436.17361; found
436.17340.
5-tert-Butyl 1-[2-(Methylsulfanyl)ethyl] 2-{[(Benzyloxy)carbonyl]-
amino}pentanedioate (22b): Synthesised according to General Pro-
cedure B. Purification by column chromatography (silica gel;
CH2Cl2/MeOH, 98:2) gave 22b (0.39 g, 0.95 mmol, 80%) as a
colourless liquid. 1H NMR (400 MHz, CDCl3): δ = 1.43 [s, 9 H,
C(CH3)3], 1.96 (mc, 1 H, NHCHCHCH2), 2.14 (s, 3 H, SCH3),
Isopropyl Benzoate (25a):[22] Synthesised according to General Pro-
cedure B. Purification by column chromatography (silica gel;
CH2Cl2) to give 25a (0.59 g, 3.60 mmol, 88%) as a colourless li-
quid. 1H NMR (400 MHz, CDCl3): δ = 1.36 (s, 3 H, CH3), 1.37 (s,
3 H, CH3), 5.25 [sept, J = 6.3 Hz, 1 H, OCH(CH3)2], 7.40–7.45 (m,
2 H, ArH), 7.51–7.56 (m, 1 H, ArH), 8.02–8.06 (m, 2 H, ArH) ppm.
13C NMR (100 MHz, CDCl3): δ = 22.0, 68.4, 128.3, 129.6, 131.0,
132.7, 166.2 ppm. MS (GC/MS-EI): m/z (%) = 105.1 (100) [M –
OCH(CH3)2]+, 164.1 (32) [M+]. HRMS (+ APCI, MeOH): m/z
calcd. for C10H13O2 [M + H]+ 165.09155; found 165.09180.
2.15–2.22 (m,
1 H, NHCHCHCH2), 2.25–2.41 (m, 2 H,
CH2COOtBu), 2.72 (t, J = 6.4 Hz, 2 H, CH2SCH3), 4.30 (t, J =
6.4 Hz, 2 H, CH2CH2SCH3), 4.39 (mc, 1 H, NHCH), 5.11 (s, 2 H,
CH2Ph), 5.41 (mc, 1 H, NH), 7.29–7.38 (m, 5 H, ArH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 15.8, 27.6, 28.3, 31.5, 32.4, 53.7,
63.9, 67.1, 80.9, 128.1, 128.2, 128.3, 128.6, 136.3, 156.0, 171.9,
172.0 ppm. MS (+ ESI): m/z (%) = 434.2 (100) [M + Na]+. HRMS
(+ ESI, MeOH): m/z calcd. for C20H29NO6NaS [M + Na]+
434.16133; found 434.16110.
5-tert-Butyl 1-Propan-2-yl 2-(Benzyloxycarbonylamino)pentane-
dioate (25b): Synthesised according to General Procedure B. Purifi-
cation by column chromatography (silica gel, CH2Cl2/MeOH, 98:2)
gave 25b (0.36 g, 0.95 mmol, 80%) as a colourless liquid. 1H NMR
(400 MHz, CDCl3): δ = 1.21–1.27 [m, 6 H, CH(CH3)2], 1.43 [s, 9
H, C(CH3)3], 1.86–1.98 (m, 1 H, NHCHCHCH2), 2.13 (mc, 1 H,
NHCHCHCH2), 2.21–2.39 (m, 2 H, CH2COOtBu), 4.33 (mc, 1 H,
NHCH), 5.04 [sept, J = 6.3 Hz, 1 H, CH(CH3)2], 5.10 (s, 2 H,
CH2Ph), 5.40 (mc, 1 H, NH), 7.28–7.37 (m, 5 H, ArH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 21.8, 27.9, 28.1, 31.5, 53.7, 67.0,
69.4, 80.8, 128.1, 128.2, 128.6, 136.4, 156.0, 171.5, 172.1 ppm. MS
(+ ESI): m/z (%) = 402.2 (100) [M + Na]+. HRMS (+ ESI, MeOH):
m/z calcd. for C20H29NO6Na [M + Na]+ 402.18926; found
402.18890.
2-(Trimethylsilanyl)ethyl Benzoate (23a): Synthesised according to
General Procedure B. Purification by column chromatography (sil-
ica gel; CH2Cl2) gave 23a (0.70 g, 3.15 mmol, 88%) as a colourless
liquid. 1H NMR (400 MHz, CDCl3): δ = 0.09 [s, 9 H, Si(CH3)3],
1.11–1.16 [m,
2
H, CH2Si(CH3)3], 4.39–4.45 [m,
2
H,
CH2CH2Si(CH3)3], 7.40–7.45 (m, 2 H, ArH), 7.51–7.56 (m, 1 H,
ArH), 8.02–8.06 (m, 2 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 1.3, 17.5, 63.3, 128.4, 129.6, 130.8, 132.8, 166.9 ppm.
MS (GC/MS-CI, NH3): m/z (%) = 195.1 (100) [M + NH4 – (CH3)
3]+, 240.2 (52) [M + NH4]+. C12H18O2Si (222.36): calcd. C 64.82,
H 8.16; found C 64.48, H 8.09.
5-tert-Butyl 1-[2-(Trimethylsilyl)ethyl] 2-{[(Benzyloxy)carbonyl]-
amino}pentanedioate (23b): Synthesised according to General Pro-
cedure B. Purification by column chromatography (silica gel,
CH2Cl2/MeOH, 98:2) gave 23b (0.31 g, 0.71 mmol, 95%) as a
colourless liquid. 1H NMR (400 MHz, CDCl3): δ = 0.05 [s, 9 H,
Si(CH3)3], 1.00 [t, J = 8.4 Hz, 2 H, CH2Si(CH3)3], 1.43 [s, 9 H,
4-Oxo-4-phenyl-N,N-bis(pyridin-2-ylmethyl)butyramide
(26a):
Benzoyl propionic acid was coupled with bpa in the presence of
TBTU and DIPEA as described in General Procedure A. The re-
sulting amide 26a (0.56 g, 1.56 mmol, 89%) was isolated after puri-
fication by column chromatography (silica gel; CH2Cl2 ǞCH2Cl2/
MeOH, 96:4). 1H NMR (300 MHz, CDCl3): δ = 2.93 (t, J = 6.4 Hz,
2 H, NCOCH2CH2), 3.41 (t, J = 6.4 Hz, 2 H, NCOCH2CH2), 4.78
(s, 2 H, CH2Py), 4.82 (s, 2 H, CH2Py), 7.14 (ddd, J = 7.6, 4.9,
1.2 Hz, 1 H, ArH), 7.18 (ddd, J = 7.6, 4.9, 1.2 Hz, 1 H, ArH), 7.31
(mc, 2 H, ArH), 7.41–7.47 (m, 2 H, ArH), 7.51–7.56 (m, 2 H, ArH),
7.62 (ddd, J = 7.7, 7.7, 1.8 Hz, 1 H, ArH), 7.69 (ddd, J = 7.7, 7.7,
1.8 Hz, 1 H, ArH), 7.98–8.02 (m, 2 H, ArH), 8.48 (mc, 1 H, ArH),
8.56 (mc, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.6,
34.1, 51.9, 53.2, 120.9, 122.3, 122.4, 128.1, 128.7, 133.0, 136.9,
149.2, 149.9, 156.8, 157.4, 172.8, 199.2 ppm. MS (CI, NH3): m/z
(%) = 360.2 (100) [M + H]+. HRMS (CI, NH3): m/z calcd. for
C22H22N3O2 [M + H]+ 360.17120; found 360.17100.
C(CH3)3], 1.94 (mc,
1 H, NHCHCHCH2), 2.15 (mc, 1 H,
NHCHCHCH2), 2.22–2.34 (m, 2 H, CH2COOtBu), 4.22 [mc, 2 H,
CH2CH2Si(CH3)3], 4.35 (mc, 1 H, NHCH), 5.10 (s, 2 H, CH2Ph),
5.39 (mc, 1 H, NH), 7.28–7.36 (m, 5 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = –1.4, 17.5, 27.9, 28.2, 31.6, 53.8, 64.1, 67.1,
80.9, 128.1, 128.2, 128.3, 128.6, 136.5, 156.0, 172.1, 172.2 ppm. MS
(+ ESI): m/z (%) = 460.2 (100) [M + Na]+; HRMS (+ ESI, MeOH):
m/z calcd. for C22H35NO6NaSi [M + Na]+ 460.21314; found
460.21310.
Phenyl Benzoate (24a):[21] Synthesised according to General Pro-
cedure B. Purification by column chromatography (silica gel;
CH2Cl2) to give 24a (0.61 g, 3.07 mmol, 75%) as a white solid, m.p.
68–70 °C. 1H NMR (400 MHz, CDCl3): δ = 7.19–7.23 (m, 2 H,
ArH), 7.24–7.28 (m, 1 H, ArH), 7.39–7.44 (m, 2 H, ArH), 7.47–
7.52 (m, 2 H, ArH), 7.59–7.64 (m, 1 H, ArH), 8.18–8.22 (m, 2 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 121.7, 125.9, 128.6,
129.5, 129.6, 130.2, 133.6, 151.0, 165.2 ppm. MS (+ APCI): m/z
(%) = 199.0 (100) [M + H]+. HRMS (+ APCI, MeOH): m/z calcd.
for C13H11O2 [M + H]+ 199.07590; found 199.07580. C13H10O2
(198.22): calcd. C 78.77, H 5.08; found C 78.79, H 5.02.
4-Hydroxy-4-phenyl-N,N-bis(pyridin-2-ylmethyl)butyramide (26b):
Keto amide 26a was reduced as described in General Procedure C.
The resulting amide 26b (0.47 g, 1.30 mmol, 81%) was obtained as
a colourless oil after purification by column chromatography (silica
gel; CH2Cl2 ǞCH2Cl2/MeOH, 90:10). 1H NMR (300 MHz,
CDCl3): δ = 2.03–2.12 (m, 1 H, CH), 2.20–2.28 (m, 1 H, CH),
2.56–2.63 (m, 1 H, CH), 2.79–2.86 (m, 1 H, CH), 4.63–4.70 (m, 2
1-tert-Butyl Phenyl 4-{[(Benzyloxy)carbonyl]amino}pentanedioate H, CH2Py), 4.77–4.86 (m, 3 H, CH2Py, CHOH), 7.14–7.25 (m, 4
(24b): Synthesised according to General Procedure B. Purification
by column chromatography (silica gel; CH2Cl2/MeOH, 98:2) to
give 24b (0.35 g, 0.85 mmol, 72%) as a white solid, m.p. 68–70 °C.
1H NMR (400 MHz, CDCl3): δ = 1.45 [s, 9 H, C(CH3)3], 2.13 (mc,
H, ArH), 7.28–7.38 (m, 5 H, ArH), 7.61–7.67 (m, 2 H, ArH), 8.49
(ddd, J = 4.9, 1.7, 0.9 Hz, 1 H, ArH), 8.55 (ddd, J = 4.9, 1.7,
0.9 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 29.5,
34.6, 51.5, 53.3, 73.1, 121.8, 122.5, 122.9, 122.9, 125.8, 127.2, 128.4,
1 H, NHCHCHCH2), 2.26–2.36 (m, 1 H, NHCHCHCH2), 2.36– 137.0, 137.2, 145.0, 149.1, 150.0, 156.3, 157.3, 174.6 ppm. MS (+
2.51 (m, 2 H, CH2COOtBu), 4.63 (mc, 1 H, NHCH), 5.14 (s, 2 H, ESI): m/z (%) = 384.2 (100) [M + Na]+. MS (– ESI): m/z (%) =
CH2Ph), 5.51 (mc, 1 H, NH), 7.10 (mc, 2 H, ArH), 7.22–7.26 (m, 360.2 (100) [M – H]–. HRMS (+ ESI, MeOH): m/z calcd. for
6970
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Transfer of Chelating Amides into Esters and Lactones
C22H23N3O2Na [M + Na]+ 384.16880; found 384.16830. HRMS
methyl-4-hexanoic acid (0.14 g, 0.89 mmol, 15% over two steps;
(– ESI, MeOH): m/z calcd. for C22H22N3O2 [M – H]– 360.17120; Lit. 38%[26]) was obtained as white needles, m.p. 66–67 °C. 1H
found 360.17180.
NMR (400 MHz, CDCl3): δ = 1.16 [s, 9 H, C(CH3)3], 2.62 (t, J =
6.4 Hz, 2 H, CH2), 2.81 (t, J = 6.4 Hz, 2 H, CH2) ppm. 13C NMR
(100 MHz, CDCl3): δ = 26.6, 28.1, 31.5, 44.1, 178.6, 214.1 ppm.
MS (– APCI): m/z (%) = 157.1 (100) [M – H]–. HRMS (– APCI,
MeOH): m/z calcd. for C8H13O3 [M – H]– 157.08647; found
157.08680.
5-Phenyldihydro-2(3H)-furanone (26c):[23] The bpa precursor 26b
was transformed into the pertinent lactone 26c according to Gene-
ral Procedure E. Evaporation of the solvent gave lactone 26c
(59.6 mg, 0.37 mmol, 98%) as a colourless oil. 1H NMR (400 MHz,
CDCl3): δ = 2.13–2.25 (m, 1 H, CH), 2.60–2.74 (m, 3 H, CH2, CH),
5.49–5.52 (m, 1 H, CHPh), 7.31–7.41 (m, 5 H, ArH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 28.9, 30.9, 81.2, 125.2, 128.4, 128.7,
139.3, 176.8 ppm. MS (+ APCI): m/z (%) = 163.1 (100) [M + H]+.
MS (– APCI): m/z (%) = 177.1 (100) [M + O – H]–. HRMS
(+ APCI, MeOH): m/z calcd. for C10H11O2 [M + H]+ 163.07590;
found 163.07610. HRMS (– APCI, MeOH): m/z calcd. for
C10H9O3 [M + O – H]– 177.05517; found 177.05520.
5,5-Dimethyl-4-oxo-N,N-bis(pyridin-2-ylmethyl)hexanamide (28a):
Pivaloyl propionic acid was coupled with bpa in the presence of
TBTU and DIPEA as described in General Procedure A. The re-
sulting amide 28a (0.18 g, 0.53 mmol, 73%) was isolated as an al-
most colourless gum after purification by column chromatography
1
(silica gel; CH2Cl2 ǞCH2Cl2/MeOH, 90:10). H NMR (400 MHz,
CDCl3): δ = 1.17 [s, 9 H, C(CH3)3], 2.71 (t, J = 6.3 Hz, 2 H, CH2),
2.92 (t, J = 6.3 Hz, 2 H, CH2), 4.76 (s, 4 H, 2ϫCH2Py), 7.11–7.18
(m, 2 H, ArH), 7.25–7.28 (m, 2 H, ArH), 7.60 (ddd, J = 7.7, 7.7,
1.8 Hz, 1 H, ArH), 7.66 (ddd, J = 7.7, 7.7, 1.8 Hz, 1 H, ArH), 8.47
(ddd, J = 4.8, 1.8, 0.9 Hz, 1 H, ArH), 8.54 (ddd, J = 4.8, 1.8,
0.9 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 26.5,
26.6, 27.1, 32.0, 43.9, 51.5, 53.1, 53.4, 120.9, 122.2, 122.2, 122.4,
136.8, 136.9, 149.1, 149.8, 156.7, 157.4, 173.0 ppm. MS (+ APCI):
m/z (%) = 340.2 (100) [M + H]+. HRMS (+ APCI, MeOH): m/z
calcd. for C20H26N3O2 [M + H]+ 340.20250; found 340.20230.
4-Oxo-N,N-bis(pyridin-2-ylmethyl)pentanamide (27a): Levulinic
acid was coupled with bpa in the presence of TBTU and DIPEA as
described in General Procedure A. The resulting amide 27a (0.55 g,
1.85 mmol, 81%) was isolated after purification by column
chromatography (silica gel; CH2Cl2 ǞCH2Cl2/MeOH, 96:4). 1H
NMR (300 MHz, CDCl3): δ = 2.18 (s, 3 H, CH3), 2.69–2.73 (m, 2
H, CH2), 2.79–2.82 (m, 2 H, CH2), 4.72 (s, 4 H, 2ϫCH2Py), 7.09–
7.17 (m, 2 H, ArH), 7.23–7.26 (m, 2 H, ArH), 7.58 (ddd, J = 7.7,
7.7, 1.8 Hz, 1 H, ArH), 7.64 (ddd, J = 7.7, 7.7, 1.8 Hz, 1 H, ArH),
8.45 (ddd, J = 4.9, 1.8, 0.9 Hz, 1 H, ArH), 8.52 (ddd, J = 4.8, 1.8,
1.0 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.1,
29.9, 38.1, 51.5, 53.0, 120.9, 122.2, 122.2, 122.4, 136.7, 136.8, 149.0,
149.7, 156.5, 157.3, 172.6, 207.6 ppm. MS (+ APCI): m/z (%) =
298.2 (100) [M + H]+. HRMS (+ APCI, MeOH): m/z calcd. for
C17H20N3O2 [M + H]+ 298.15555; found 298.15590.
4-Hydroxy-5,5-dimethyl-N,N-bis(pyridin-2-ylmethyl)hexanamide
(28b): The β-keto amide 28a was reduced according to General
Procedure C. The pertinent β-hydroxy amide 28b (0.13 g,
0.38 mmol, 94%) was obtained as a colourless gum after purifica-
tion by column chromatography (silica ge; CH2Cl2 Ǟ CH2Cl2/
MeOH, 90:10). 1H NMR (400 MHz, CDCl3): δ = 0.91 [s, 9 H,
C(CH3 )3 ], 1.72 (dddd, J = 14.0, 10.9, 7.0, 5.1 Hz, 1 H,
CHCH2CONR2), 1.96 (dddd, J = 13.9, 8.4, 5.4, 2.3 Hz, 1 H,
CHCH2 CONR2 ), 2.58 (ddd, J = 15.9, 7.0, 5.3 Hz, 1 H,
CH2 CHCONR2 ), 2.82 (ddd, J = 15.9, 8.4, 5.1 Hz, 1 H,
CH2CHCONR2), 3.21 (dd, J = 10.9, 2.2 Hz, 1 H, CH), 3.73 (br. s,
1 H, OH), 4.62–4.71 (m, 2 H, CH2Py), 4.79–4.85 (m, 2 H, CH2Py),
7.13–7.21 (m, 3 H, ArH), 7.28–7.30 (m, 1 H, ArH), 7.60 (ddd, J =
7.7, 7.7, 1.8 Hz, 1 H, ArH), 7.65 (ddd, J = 7.7, 7.7, 1.8 Hz, 1 H,
ArH), 8.48 (ddd, J = 4.9, 1.8, 0.9 Hz, 1 H, ArH), 8.54–8.56 (m, 1
H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.8, 26.8, 30.3,
35.0, 51.2, 53.2, 63.7, 78.8, 121.7, 122.3, 122.7, 136.8, 137.0, 149.1,
149.9, 156.5, 157.4, 174.9 ppm. MS (– APCI): m/z (%) = 376.2 (100)
[M + Cl]–. HRMS (+ APCI, MeOH): m/z calcd. for C20H28N3O2
[M + H]+ 342.21815; found 342.21840. HRMS (– APCI, MeOH):
m/z calcd. for C20H27N3O2Cl [M + Cl]– 376.17918; found
376.17980.
4-Hydroxy-N,N-bis(pyridin-2-ylmethyl)pentanamide (27b): Com-
pound 27a was reduced according to General Procedure C. The
pertinent hydroxy amide 27b (0.49 g, 1.64 mmol, 79%) was ob-
tained as a colourless oil after purification by column chromatog-
raphy (silica gel; CH2Cl2 ǞCH2Cl2/MeOH, 90:10). 1H NMR
(400 MHz, CDCl3): δ = 1.18 (d, J = 6.2 Hz, 3 H, CH3), 1.74 (dddd,
J = 14.2, 8.9, 6.7, 5.3 Hz, 1 H, CH), 1.94 (dddd, J = 14.1, 8.6, 5.5,
3.1 Hz, 1 H, CH), 2.54 (ddd, J = 15.9, 6.7, 5.5 Hz, CH), 2.82 (ddd,
J = 16.0, 8.6, 5.4 Hz, 1 H, CH), 3.84 (tdd, J = 15.3, 9.3, 3.1 Hz, 1
H, CH), 4.61–4.67 (m, 2 H, CH2Py), 4.78–4.83 (m, 2 H, CH2Py),
7.11–7.14 (m, 1 H, ArH), 7.16–7.20 (m, 2 H, ArH), 7.26–7.28 (m,
1 H, ArH), 7.58 (ddd, J = 7.7, 7.7, 1.8 Hz, 1 H, ArH), 7.63 (ddd,
J = 7.7, 7.7, 1.8 Hz, 1 H, ArH), 8.46 (ddd, J = 4.9, 1.8, 0.9 Hz, 1
H, ArH), 8.54 (ddd, J = 4.7, 1.8, 1.1 Hz, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 23.5, 29.3, 34.2, 51.3, 53.1, 68.8, 121.7,
122.3, 122.6, 122.7, 136.7, 137.0, 149.0, 149.8, 156.3, 157.3,
174.3 ppm. MS (+ APCI): m/z (%) = 300.2 (100) [M + H]+. MS
(– APCI): m/z (%) = 334.1 (100) [(M + Cl]–. HRMS (+ APCI,
MeOH): m/z calcd. for C17H22N3O2 [M + H]+ 300.17120; found
300.17130.
5-tert-Butyl-4,5-dihydro-2(3H)-furan (28c):[26,27] The bpa precursor
28b was transformed into the pertinent lactone 28c according to
General Procedure E. Evaporation of the solvent led to lactone
28c (35.2 mg, 0.25 mmol, 75%) as a colourless liquid. 1H NMR
(400 MHz, CDCl3): δ = 0.95 [s, 9 H, C(CH3)3], 1.92–2.02 (m, 1 H,
CH), 2.08–2.16 (m, 1 H, CH), 2.47–2.59 (m, 2 H, CH2), 4.19 (dd,
J = 8.8, 6.9 Hz, 1 H, CHtBu) ppm. 13C NMR (100 MHz, CDCl3):
δ = 23.1, 25.1, 29.5, 34.0, 88.4, 177.5 ppm. MS (+ APCI): m/z (%)
= 143.1 (100) [M + H]+. HRMS (+ APCI, MeOH): m/z calcd. for
C8H15O2 [M + H]+ 143.10720; found 143.10730. HRMS (+ APCI,
MeOH): m/z calcd. for C8H18NO2 [M + NH4]+ 160.13375; found
160.13380.
5-Methyloxolan-2-one (27c):[24] The bpa precursor 27b was trans-
formed into the pertinent lactone 27c according to General Pro-
cedure E. Evaporation of the solvent gave lactone 27c (30.0 mg,
1
0.30 mmol, 71%). H NMR (400 MHz, CDCl3): δ = 1.41 (d, J =
6.3 Hz, 3 H, CH3), 1.83 (m, 1 H, CH), 2.35 (m, 1 H, CH), 2.54 (m,
2 H, CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.2, 29.2, 29.8,
77.4, 177.3 ppm. MS (+ APCI): m/z (%) = 101.1 (100) [M + H]+.
HRMS (+ APCI, CH2Cl2): m/z calcd. for C5H9O2 [M + H]+
101.06025; found 101.06030.
5,5-Dimethyl-4-oxohexanoic Acid:[25] The β-keto carboxylic acid
was prepared according to a reported procedure in two steps from
α-bromo-pinacolone and dimethyl malonate. The resulting 5,5-di-
2-Benzoyl-4-methyl-N,N-bis(pyridin-2-ylmethyl)benzamide (29a): 2-
Benzoyl-5-methylbenzoic acid was coupled with bpa in the presence
of TBTU and DIPEA as described in General Procedure A. The
resulting amide 29a (0.89 g, 2.11 mmol, 85%) was isolated as a yel-
Eur. J. Org. Chem. 2014, 6963–6974
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6971

W. Bannwarth et al.
FULL PAPER
low gum after purification by column chromatography (silica gel;
9 H, ArH), 7.60–7.67 (m, 2 H, ArH), 8.47 (ddd, J = 4.9, 1.8, 1.0 Hz,
1 H, ArH), 8.54 (ddd, J = 4.8, 1.8, 0.9 Hz, 1 H, ArH) ppm. 13C
CH2Cl2 ǞCH2Cl2/MeOH, 96:4). 1H NMR (400 MHz, CDCl3): δ
= 2.41 (s, 3 H, CH3), 4.67 (s, 2 H, CH2Py), 4.86 (s, 2 H, CH2Py), NMR (100 MHz, CDCl3): δ = 21.1, 32.6, 38.6, 38.7, 51.3, 53.1,
7.11–7.16 (m, 2 H, ArH), 7.23–7.25 (m, 2 H, ArH), 7.27–7.31 (m, 73.6, 120.9, 122.3, 122.5, 122.7, 125.8, 127.2, 128.3, 136.9, 136.9,
1 H, ArH), 7.37–7.44 (m, 2 H, ArH), 7.47–7.50 (m, 2 H, ArH), 144.9, 148.9, 149.8, 156.7, 157.3, 174.1 ppm. MS (+ ESI): m/z (%)
7.60–7.66 (m, 3 H, ArH), 7.74–7.77 (m, 2 H, ArH), 8.45 (ddd, J = = 398.2 (100) [M + Na]+. MS (– ESI): m/z (%) = 374.2 (100) [M –
4.9, 1.8, 0.9 Hz, 1 H, ArH), 8.53 (ddd, J = 4.8, 1.8, 0.9 Hz, 1 H,
H]–. HRMS (+ ESI, MeOH): m/z calcd. for C23H25N3O2Na [M +
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.7, 50.3, 54.2, Na]+ 398.18445; found 398.18390. HRMS (– ESI, MeOH): m/z
122.0, 122.1, 122.3, 122.6, 127.6, 128.3, 129.5, 130.3, 134.5, 136.6,
136.8, 137.1, 137.9, 144.0, 148.8, 149.6, 156.4, 157.0, 171.4 ppm.
MS (+ APCI): m/z (%) = 422.2 (100) [M + H]+. HRMS (+ APCI,
MeOH): m/z calcd. for C27H24N3O2 [M + H]+ 422.18685; found
422.18690.
calcd. for C23H24N3O2 [M – H]– 374.18685; found 374.18720.
6-Phenyloxan-2-one (30c):[24] The γ-lactone 30c was synthesised
from bpa precursor 30b according to General Procedure E. The
lactone (35.5 mg, 0.20 mmol, 88%) was isolated as a colourless oil.
1H NMR (400 MHz, CDCl3): δ = 1.82–1.92 (m, 1 H, CH), 1.95–
2.02 (m, 2 H, CH2), 2.13–2.20 (m, 1 H, CH), 2.53–2.61 (m, 1 H,
CH), 2.67–2.75 (m, 1 H, CH), 5.35 (dd, J = 10.4, 3.4 Hz, 1 H,
CHPh), 7.30–7.40 (m, 5 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 18.5, 29.4, 30.4, 81.6, 125.6, 128.2, 128.5, 139.7,
171.3 ppm. MS (+ APCI): m/z (%) = 177.1 (100) [M + H]+. HRMS
2-[Hydroxy(phenyl)methyl]-4-methyl-N,N-bis(pyridin-2-ylmethyl)-
benzamide (29b): Compound 29a was reduced according to General
Procedure C. The resulting hydroxy amide 29b (0.79 g, 1.87 mmol,
88%) was obtained as a pale-yellow gum after purification with
column chromatography (silica gel; CH2Cl2 Ǟ CH2Cl2/MeOH,
1
95:5). H NMR (400 MHz, CDCl3): δ = 2.35 (s, 3 H, CH3), 4.53 (+ APCI, MeOH): m/z calcd. for C11H13O2 [M + H]+ 177.09155;
(s, 2 H, CH2Py), 4.87 (s, 2 H, CH2Py), 6.21 (s, 1 H, CH), 7.12–7.47 found 177.09160.
(m, 12 H, ArH), 7.61–7.68 (m, 2 H, ArH), 8.49–8.51 (m, 1 H, ArH),
5-Oxo-N,N-bis(pyridin-2-ylmethyl)hexanamide (31a): 4-Acetyl
8.56–8.57 (m, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ =
butyric acid was coupled with bpa according to General Procedure
21.2, 54.6, 82.8, 122.2, 122.4, 122.9, 125.7, 126.5, 127.1, 128.8,
A. The pertinent keto amide 31a (0.72 g, 0.23 mmol, 96%) was
129.4, 129.5, 129.7, 133.5, 134.3, 136.6, 137.1, 143.3, 149.1, 149.4,
isolated as a colourless gum after purification by column
149.9 ppm. MS (+ ESI, MeOH): m/z (%) = 446.2 (100) [M +
chromatography (silica gel; CH2Cl2 ǞCH2Cl2/MeOH, 90:10). 1H
Na]+. HRMS (+ APCI): m/z calcd. for C27H25N3O2Na [M +
NMR (400 MHz, CDCl3): δ = 1.91 (tt, J = 7.1, 7.1 Hz, 2 H,
Na]+ 446.18445; found 446.18410.
CH2CH2CH2), 2.07 (s, 3 H, CH3), 2.46 (t, J = 7.1 Hz, 2 H,
6-Methyl-3-phenyl-1,3-dihydro-2-benzofuran-1-one (29c):[28] The CH2CH2CH2), 2.49 (t, J = 7.1 Hz, 2 H, CH2CH2CH2), 4.66 (s, 2
bpa precursor 29b was transformed into the pertinent lactone 29c
according to General Procedure E. Evaporation of the solvent led
H, CH2Py), 4.72 (s, 2 H, CH2Py), 7.09–7.15 (m, 3 H, ArH), 7.23–
7.25 (m, 1 H, ArH), 7.56–7.62 (m, 2 H, ArH), 8.44 (ddd, J = 4.9,
to lactone 29c (49.8 mg, 0.22 mmol, 94%) as a white solid, m.p. 1.8, 0.9 Hz, 1 H, ArH), 8.51 (ddd, J = 4.8, 1.8, 0.9 Hz, 1 H,
1
126–127 °C. H NMR (400 MHz, CDCl3): δ = 2.35 (s, 3 H, CH3), ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.2, 29.7, 31.9,
6.37 (s, 1 H, ArCHPh), 7.14–7.19 (m, 4 H, ArH), 7.30–7.33 (m, 1 38.5, 42.6, 51.2, 52.9, 120.8, 122.1, 122.4, 136.6, 136.7, 149.0, 149.8,
H, ArH), 7.52–7.56 (m, 1 H, ArH), 7.63 (ddd, J = 7.5, 7.5, 1.2 Hz,
156.6, 157.4, 173.2, 208.4 ppm. MS (+ ESI): m/z (%) = 334.2 (100)
1 H, ArH), 7.94–7.96 (m, 1 H, ArH) ppm. 13C NMR (100 MHz, [M + Na]+. HRMS (+ ESI, MeOH): m/z calcd. for C18H21N3O2Na
CDCl3): δ = 21.2, 82.7, 122.8, 125.5, 125.7, 127.0, 129.2, 129.6,
133.4, 134.2, 139.3, 149.8, 170.5 ppm. MS (+ ESI): m/z (%) = 247.1
(100) [M + Na]+. HRMS (+ ESI, MeOH): m/z calcd. for
C15H12O2Na [M + Na]+ 247.07350; found 247.07360.
[M + Na]+ 334.15315; found 334.15330.
5-Hydroxy-N,N-bis(pyridin-2-ylmethyl)hexanamide (31b): Com-
pound 31a was reduced according to General Procedure C. The
pertinent hydroxy amide 31b (0.49 g, 1.57 mmol, 72%) was isolated
5-Oxo-5-phenyl-N,N-bis(pyridin-2-ylmethyl)pentanamide (30a): as a colourless gum after purification with column chromatography
1
Benzoyl butyric acid was coupled with bpa according to General
Procedure A. The resulting keto amide 30a (0.96 g, 2.57 mmol,
84%) was obtained as a colourless gum after purification by col-
(silica gel; CH2Cl2 ǞCH2Cl2/MeOH, 90:10). H NMR (400 MHz,
CDCl3): δ = 1.15 (d, J = 6.2 Hz, 3 H, CH3), 1.42–1.50 (m, 2 H,
CH2), 1.71–1.88 (m, 2 H, CH2), 2.49 (t, J = 7.1 Hz, 2 H, CH2),
umn chromatography (silica gel; CH2Cl2 ǞCH2Cl2/MeOH, 94:6). 3.76 (qt, J = 12.4, 6.2 Hz, 1 H, CHOH), 4.70–4.80 (m, 4 H,
1H NMR (400 MHz, CDCl3): δ = 2.13 (tt, J = 10.4, 7.0 Hz, 2 H,
2ϫCH2Py), 7.12–7.19 (m, 3 H, ArH), 7.27–7.29 (m, 1 H, ArH),
CH2CH2CH2), 2.61 (t, J = 7.0 Hz, 2 H, CH2CH2CH2), 3.09 (t, J 7.60 (ddd, J = 7.7, 7.7, 1.8 Hz, 1 H, ArH), 7.63 (ddd, J = 7.7, 7.7,
= 7.0 Hz, 2 H, CH2CH2CH2), 4.73 (s, 2 H, CH2Py), 4.79 (s, 2 H, 1.8 Hz, 1 H, ArH), 8.47 (ddd, J = 4.9, 1.8, 0.9 Hz, 1 H, ArH), 8.54
CH2Py), 7.13–7.19 (m, 3 H, ArH), 7.31–7.34 (m, 1 H, ArH), 7.42– (ddd, J = 4.8, 1.8, 1.0 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz,
7.47 (m, 2 H, ArH), 7.53–7.66 (m, 3 H, ArH), 7.94–7.97 (m, 2 H,
ArH), 8.48–8.51 (m, 2 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.8, 32.1, 37.7, 51.2, 53.0, 120.9, 122.3, 122.4, 122.7,
CDCl3): δ = 20.9, 23.4, 32.7, 38.8, 51.4, 53.1, 67.0, 120.9, 122.2,
122.5, 122.5, 136.7, 136.8, 149.1, 149.8, 156.7, 157.4, 174.1 ppm.
MS (+ ESI): m/z (%) = 336.2 (100) [M + Na]+. HRMS (+ ESI,
128.1, 128.5, 133.0, 136.8, 136.9, 149.8, 156.6, 157.3, 173.5, MeOH): m/z calcd. for C18H23N3O2Na [M + Na]+ 336.16880;
200.0 ppm. MS (+ APCI): m/z (%) = 374.2 (100) [M + H]+. HRMS
(+ APCI, MeOH): m/z calcd. for C23H24N3O2 [M + H]+ 374.18685;
found 374.18660.
found 336.16910. HRMS (– ESI, MeOH): m/z calcd. for
C18H22N3O2 [M – H]– 312.17120; found 312.17130.
6-Methyloxan-2-one (31c):[24] The bpa precursor 31b was trans-
formed into the pertinent lactone 31c according to General Pro-
cedure E. Evaporation of the solvent led to lactone 31c (18.3 mg,
5-Hydroxy-5-phenyl-N,N-bis(pyridin-2-ylmethyl)pentanamide (30b):
Compound 30a was reduced according to General Procedure C.
The pertinent hydroxy amide (0.69 g, 1.84 mmol, 82%) was isolated 0.16 mmol, 64%) as a colourless oil. 1H NMR (400 MHz, CDCl3):
as a colourless gum after purification with column chromatography
(silica gel; CH2Cl2 ǞCH2Cl2/MeOH, 90:10). H NMR (400 MHz,
CDCl3): δ = 1.70–1.87 (m, 4 H, 2ϫCH2), 2.46–2.62 (m, br. s, 3 H,
CH2, OH), 4.66–4.82 (m, 5 H, 2ϫCH2Py, CHOH), 7.14–7.34 (m,
δ = 1.36 (d, J = 6.3 Hz, 3 H, CH3), 1.47–1.56 (m, 1 H, CH), 1.78–
1.94 (m, 3 H, CH2, CH), 2.38–2.46 (m, 1 H, CH), 2.52–2.60 (m, 1
H, CH), 4.43 (mc, 1 H, CHCH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 18.5, 21.6, 29.2, 29.6, 38.6, 76.8, 171.7 ppm. MS
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Transfer of Chelating Amides into Esters and Lactones
(+ APCI): m/z (%) = 132.1 (100) [M + NH4]+. HRMS (+ APCI, 13C NMR (100 MHz, CDCl3): δ = 19.4, 26.8, 27.5, 33.3, 34.3, 89.1,
MeOH): m/z calcd. for C6H14NO2 [M + NH4]+ 132.10245; found
132.10240. HRMS (+ APCI, MeOH): m/z calcd. for C6H11O2 [M
+ H]+ 115.07590; found 115.07580.
127.5, 127.8, 128.2, 136.3, 171.3 ppm. MS (+ APCI): m/z (%) =
222.1 (100) [M + NH4]+. HRMS (+ APCI, MeOH): m/z calcd. for
C13H20NO2 [M + NH4]+ 222.14940; found 222.14950. HRMS
(+ APCI, MeOH): m/z calcd. for C13H17O2 [M + H]+ 205.12285;
found 205.12300.
4,4-Dimethyl-5-oxo-5-phenylpentanoic Acid:[29] Ethyl 4,4-dimethyl-
5-oxo-5-phenylpentanoate was synthesised from isobutyrophenone
and ethyl 3-bromopropionate in the presence of NaH. The crude
ethyl ester was then heated to reflux in a solution of sodium
hydroxide in MeOH (35 mL) and water (5 mL). After cooling to
room temperature, the mixture was diluted in water and washed
6-Oxo-6-phenyl-N,N-bis(pyridin-2-ylmethyl)hexanamide (33a):
Benzoyl pentanoic acid was coupled with bpa according to General
Procedure A. The pertinent keto amide 33a (0.66 g, 1.71 mmol,
93%) was isolated as a colourless gum after purification by column
with CH. The aqueous phase was acidified with 2 n HCl, extracted chromatography (silica gel; CH2Cl2 ǞCH2Cl2/MeOH, 90:10). 1H
with CH2Cl2 (3ϫ 60 mL) and the combined organic phases were
dried with Na2SO4. The resulting carboxylic acid (1.29 g,
5.84 mmol, 58% over two steps) was obtained as a pale-yellow oil.
1H NMR (400 MHz, CDCl3): δ = 1.35 (s, 6 H, 2ϫCH3), 2.08–2.12
NMR (400 MHz, CDCl3): δ = 1.75–1.80 (m, 4 H, CH2CH2), 2.51
(t, J = 6.6 Hz, 2 H, CH2), 2.97 (t, J = 7.0 Hz, 2 H, CH2), 4.71 (s,
2 H, CH2Py), 4.78 (s, 2 H, CH2Py), 7.13–7.18 (m, 3 H, ArH), 7.29–
7.31 (m, 1 H, ArH), 7.42–7.46 (m, 2 H, ArH), 7.52–7.56 (m, 1 H,
(m, 2 H, CH2), 2.31–2.36 (m, 2 H, CH2), 7.38–7.42 (m, 2 H, ArH), ArH), 7.60–7.66 (m, 2 H, ArH), 7.91–7.94 (m, 2 H, ArH), 8.48–
7.44–7.48 (m, 1 H, ArH), 7.65–7.68 (m, 2 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 25.8, 29.8, 35.2, 47.0, 127.6, 128.2, 131.1,
138.5, 179.4, 208.1 ppm. MS (+ APCI): m/z (%) = 221.1 (100) [M
8.49 (m, 1 H, ArH), 8.54–8.55 (m, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 23.9, 24.8, 32.9, 38.3, 51.4, 53.1, 120.7,
122.3, 122.4, 122.5, 128.0, 128.5, 132.9, 136.7, 136.8, 137.0, 149.1,
+ H]+. MS (– APCI): m/z (%) = 255.1 (100) [M + Cl]–. HRMS 149.9, 156.8, 157.5, 173.6, 200.1 ppm. MS (+ APCI): m/z (%) =
(+ APCI, MeOH): m/z calcd. for C13H17O3 [M + H]+ 221.11777;
found 221.11780. HRMS (– APCI, MeOH): m/z calcd. for
C13H16O3Cl [M + Cl]+ 255.07880; found 255.07890.
410.2 (100) [M + Na]+. HRMS (+ APCI, MeOH): m/z calcd. for
C24H25N3O2Na [M + Na]+ 410.18445; found 410.18400.
6-Hydroxy-6-phenyl-N,N-bis(pyridin-2-ylmethyl)hexanamide (33b):
6-Oxo-6-phenyl-N,N-bis(pyridin-2-ylmethyl)hexanamide 33a was
reduced according to General Procedure C. The pertinent hydroxy
amide 33b (0.49 g, 1.26 mmol, 85%) was isolated as a colourless
gum after purification by column chromatography (silica gel;
4,4-Dimethyl-5-oxo-5-phenyl-N,N-bis(pyridin-2-ylmethyl)pentan-
amide (32a): 4,4-Dimethyl-5-oxo-5-phenylpentanoic acid 32 was
coupled with bpa according to General Procedure A. The pertinent
keto amide 32a (0.66 g, 1.65 mmol, 85%) was isolated as a colour-
less gum after purification with column chromatography (silica gel;
1
CH2Cl2 ǞCH2Cl2/MeOH, 90:10). H NMR (400 MHz, CDCl3): δ
1
CH2Cl2 ǞCH2Cl2/MeOH, 90:10). H NMR (400 MHz, CDCl3): δ
= 1.25–1.49 (m, 2 H, CH2), 1.61–1.82 (m, 4 H, 2ϫCH2), 2.41 (t,
= 1.30 (s, 6 H, 2ϫCH3), 2.18–2.22 (m, 2 H, CH2), 2.41–2.45 (m, J = 7.4 Hz, 2 H, CH2CONR2), 2.71 (br. s, 1 H, OH), 4.63–4.67 (m,
2 H, CH2), 4.64 (s, 2 H, CH2Py), 4.74 (s, 2 H, CH2Py), 7.07–7.67 1 H, CHOH), 4.67 (s, 2 H, CH2Py), 4.74 (s, 2 H, CH2Py), 7.10–
(m, 8 H, ArH), 7.53–7.69 (m, 3 H, ArH), 8.48 (ddd, J = 4.9, 1.8,
0.9 Hz, 1 H, ArH), 8.51 (ddd, J = 4.8, 1.8, 0.9 Hz, 1 H, ArH) ppm.
13C NMR (100 MHz, CDCl3): δ = 26.1, 28.9, 36.0, 38.6, 47.2, 51.4,
53.0, 120.9, 122.3, 122.4, 122.6, 127.6, 128.1, 131.0, 136.7, 136.8,
138.7, 149.0, 149.8, 156.6, 157.5, 173.6, 208.5 ppm. MS (+ ESI):
m/z (%) = 402.2 (100) [M + H]+. HRMS (+ APCI, MeOH): m/z
calcd. for C25H28N3O2 [M + H]+ 402.21815; found 402.21800.
7.17 (m, 3 H, ArH), 7.20–7.31 (m, 6 H, ArH), 7.57–7.64 (m, 2 H,
ArH), 8.44 (ddd, J = 4.9, 1.8, 0.9 Hz, ArH), 8.51 (ddd, J = 4.8,
1.8, 0.9 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ =
24.8, 25.4, 32.9, 38.7, 51.4, 53.1, 74.0, 120.6, 122.2, 122.4, 122.5,
125.8, 127.3, 128.3, 136.7, 136.8, 145.0, 149.0, 149.8, 156.8, 157.4,
173.9 ppm. MS (+ APCI): m/z (%) = 390.2 (100) [M + H]+. MS
(– APCI): m/z (%) = 424.2 (100) [M + Cl]–. HRMS (+ APCI):
m/z calcd. for C24H28N3O2 [M + H]+ 390.21815; found 390.21820.
HRMS (– APCI, MeOH): m/z calcd. for C24H27N3O2Cl [M +
Cl]– 424.17918; found 424.17990.
5-Hydroxy-4,4-dimethyl-5-phenyl-N,N-bis(pyridin-2-ylmethyl)pent-
anamide (32b): Compound 32a was reduced according to General
Procedure C. The pertinent hydroxy amide 32b (0.49 g, 1.22 mmol,
88%) was isolated as a colourless gum after purification by column
chromatography (silica gel; CH2Cl2 ǞCH2Cl2/MeOH, 90:10). 1H
7-Phenyloxepan-2-one (33c):[31,32] The bpa precursor 33b was trans-
formed into the pertinent lactone 33c according to General Pro-
NMR (400 MHz, CDCl3): δ = 1.29 (s, 6 H, 2ϫCH3), 2.16–2.22 cedure E. Evaporation of the solvent led to lactone 33c (27.3 mg,
(m, 2 H, CH2), 2.40–2.44 (m, 2 H, CH2), 4.63 (s, 2 H, CH2Py),
0.14 mmol, 79%) as a white solid, m.p. 68 °C. 1H NMR (400 MHz,
4.73 (s, 2 H, CH2Py), 7.06–7.45 (m, 9 H, ArH), 7.58–7.64 (m, 2 H, CDCl3): δ = 1.66–1.82 (m, 2 H, CH2), 1.97–2.15 (m, 4 H,
ArH), 8.47 (ddd, J = 4.9, 1.7, 0.9 Hz, 1 H, ArH), 8.49–8.51 (m, 1
H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 26.1, 28.9, 36.0,
38.6, 47.2, 51.5, 53.0, 120.9, 122.2, 122.4, 122.6, 127.6, 128.1, 131.0,
136.7, 138.7, 149.0, 149.8, 156.6, 157.5, 173.6, 208.5 ppm. MS (+
CH2CH2), 2.75–2.78 (m, 2 H, CH2), 5.29 (d, J = 9.6 Hz, 1 H,
CHPh), 7.28–7.40 (m, 5 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 22.8, 28.6, 34.9, 37.4, 82.1, 125.8, 128.1, 128.5, 140.8,
174.8 ppm. MS (+ APCI): m/z (%) = 191.1 (100) [M + H]+. HRMS
APCI): m/z (%) = 404.2 (100) [M + H]+. MS (– APCI): m/z (%) = (+ APCI, MeOH): m/z calcd. for C12H15O2 [M + H]+ 191.10720;
438.2 (100) [M + Cl]–. HRMS (+ APCI, MeOH): m/z calcd. for
C25H30N3O2 [M + H]+ 404.23380; found 404.23380. HRMS
(– APCI, MeOH): m/z calcd. for C25H29N3O2Cl [M + Cl]–
438.19483; found 438.19500.
found 191.10720.
6-Oxo-N,N-bis(pyridin-2-ylmethyl)heptanamide (34a): Acetyl pent-
anoic acid was coupled with bpa according to General Procedure
A. The pertinent keto amide 34a (0.71 g, 2.18 mmol, 84%) was
5,5-Dimethyl-6-phenyloxan-2-one (32c):[30] The bpa precursor 32b
was transformed into the pertinent lactone 32c according to Gene-
ral Procedure E. Evaporation of the solvent gave lactone 32c
isolated as a colourless gum after purification by column
chromatography (silica gel; CH2Cl2 ǞCH2Cl2/MeOH, 90:10). 1H
NMR (400 MHz, CDCl3): δ = 1.51–1.59 (m, 2 H, CH2), 1.61–1.68
(m, 2 H, CH2), 2.07 (m, 3 H, CH3), 2.39 (t, J = 7.1 Hz, 2 H, CH2),
2.43 (t, J = 7.2 Hz, 2 H, CH2), 4.67 (s, 2 H, CH2Py), 4.73 (s, 2 H,
1
(24.8 mg, 0.12 mmol, 83%) as a white solid, m.p. 100–101 °C. H
NMR (400 MHz, CDCl3): δ = 0.86 (s, 3 H, CH3), 0.95 (s, 3 H,
CH3), 1.69–1.78 (m, 1 H, CH), 1.83–1.94 (m, 1 H, CH), 2.68–2.73 CH2Py), 7.10–7.17 (m, 3 H, ArH), 7.24–7.28 (m, 1 H, ArH), 7.58
(m, 2 H, CH2), 5.08 (s, 1 H, CH), 7.23–7.38 (m, 5 H, ArH) ppm. (ddd, J = 7.7, 7.7, 1.8 Hz, 1 H, ArH), 7.61 (ddd, J = 7.7, 7.7,
Eur. J. Org. Chem. 2014, 6963–6974
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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W. Bannwarth et al.
FULL PAPER
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1.8 Hz, 1 H, ArH), 8.45 (ddd, J = 4.9, 1.8, 0.9 Hz, 1 H, ArH), 8.52
(ddd, J = 4.8, 1.8, 0.9 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 23.3, 24.5, 29.7, 32.7, 38.5, 43.4, 51.4, 53.0, 120.7,
122.2, 122.4, 122.4, 136.6, 136.7, 149.0, 149.8, 156.7, 157.4, 173.5,
208.6 ppm. MS (+ APCI): m/z (%) = 326.2 (100) [M + H]+. HRMS
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[8]
[9]
6-Hydroxy-N,N-bis(pyridin-2-ylmethyl)heptanamide (34b): Com-
pound 34a was reduced according to General Procedure C. The
pertinent hydroxy amide 34b (0.43 g, 1.31 mmol, 87%) was isolated
as a colourless gum after purification by column chromatography
[10]
1
(silica gel; CH2Cl2 ǞCH2Cl2/MeOH, 90:10). H NMR (400 MHz,
CDCl3): δ = 1.13 (d, J = 6.2 Hz, 3 H, CH3), 1.31–1.45 (m, 4 H,
2ϫCH2), 1.59–1.75 (m, 2 H, CH2), 2.00 (br. s, 1 H, OH), 3.73–
3.81 (m, 1 H, CHOH), 4.70 (s, 2 H, CH2Py), 4.75 (s, 2 H, CH2Py),
7.11–7.18 (m, 3 H, ArH), 7.27–7.29 (m, 1 H, ArH), 7.59 (ddd, J =
7.7, 7.7, 1.8 Hz, 1 H, ArH), 7.62 (ddd, J = 7.7, 7.7, 1.8 Hz, 1 H,
ArH), 8.46 (ddd, J = 4.9, 1.8, 0.9 Hz, 1 H, ArH), 8.54 (ddd, J =
4.8, 1.8, 0.9 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ
= 23.4, 24.8, 25.3, 32.9, 38.9, 51.4, 53.1, 67.5, 120.7, 122.2, 122.4,
122.5, 136.7, 136.8, 149.1, 149.8, 156.9, 157.5, 173.9 ppm. MS (+
APCI): m/z (%) = 328.2 (100) [M + H]+. HRMS (+ APCI, MeOH):
m/z calcd. for C19H26N3O2 [M + H]+ 328.20250; found 328.20230.
7-Methyloxepan-2-on (34c):[33] The bpa precursor 34b was trans-
formed into the pertinent lactone 34c according to General Pro-
cedure E. Evaporation of the solvent led to lactone 34c (27.2 mg,
0.21 mmol, 68%) as a colourless oil. 1H NMR (400 MHz, CDCl3):
δ = 1.34 (d, J = 6.4 Hz, 3 H, CH3), 1.54–1.69 (m, 3 H, CH, CH2),
1.85–1.96 (m, 3 H, CH, CH2), 2.55–2.69 (m, 2 H, CH2), 4.43 (mc,
1 H, CHOCO) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.6, 22.9,
28.3, 35.0, 36.2, 76.8, 175.5 ppm. MS (+ APCI): m/z (%) = 129.1
(100) [M + H]+. HRMS (+ APCI, MeOH): m/z calcd. for C7H13O2
[M + H]+ 129.09155; found 129.09150.
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Eur. J. Org. Chem. 2014, 6963–6974