A new robust and versatile tetradentate linker for amides to be cleaved under mild conditions by unusual complexation of the amide nitrogen to Cu ++

Article abstract of DOI:10.1002/ejoc.200900291

The concept of weakening amide bonds by the rather unusual forced complexation of nitrogen to Cu⁺⁺ is not limited to tridentate ligands and was extended in this work to tetradentate ligands as well. The use of cyclic tetradentate ligands was to no avail, but an open-chain and more-flexible tetradentate ligand allowed mild cleavage by methanolysis after complexation. The principle was applied to the development of a new linker for solid-phase chemistry, which was proven to be extremely robust, yet allowed mild cleavage after activation by Cu ⁺⁺ complexation. Its stability and versatility was demonstrated by the successful application to a whole plethora of different types of reactions. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009.

Full text of DOI:10.1002/ejoc.200900291

FULL PAPER
DOI: 10.1002/ejoc.200900291
A New Robust and Versatile Tetradentate Linker for Amides To be Cleaved
under Mild Conditions by Unusual Complexation of the Amide Nitrogen to
Cu++
Rolf A. Kramer,[a] Manuel C. Bröhmer,[a] Nina V. Forkel,[a] and W. Bannwarth*[a]
Keywords: Solid-phase synthesis / Tetradentate linkers / Amides / Cleavage reactions / Copper
The concept of weakening amide bonds by the rather un-
usual forced complexation of nitrogen to Cu++ is not limited
to tridentate ligands and was extended in this work to tetra-
dentate ligands as well. The use of cyclic tetradentate li-
gands was to no avail, but an open-chain and more-flexible
tetradentate ligand allowed mild cleavage by methanolysis
after complexation. The principle was applied to the devel-
opment of a new linker for solid-phase chemistry, which was
proven to be extremely robust, yet allowed mild cleavage af-
ter activation by Cu++ complexation. Its stability and versatil-
ity was demonstrated by the successful application to a
whole plethora of different types of reactions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
synthesis, reductive amination, Suzuki–Miyaura coupling,
and ring-closing metathesis. Meanwhile, we have extended
the range of reactions that are compatible with the linker
to Grignard reactions, Horner–Wadsworth–Emmons ole-
finations, Heck couplings, Mitsunobu reactions, Staudinger
reductions, and hydroboration (unpublished results). Sali-
ent features of linker 1 are furthermore its straightforward
preparation and its recyclability.
Introduction
Solid-phase organic chemistry has gained increasing
interest over the last decades. Originally developed for the
synthesis of oligo-2Ј-deoxynucleotides, RNA fragments,
and peptides it is being applied more and more in the realm
of synthetic organic chemistry. The main advantage is the
possibility to employ excess amounts of reagents, leading to
higher yields compared to the same reaction being per-
formed in solution with equivalent amounts of reacting
components. Time-consuming purifications can be replaced
by simple filtration of the excess amounts of reagents.
In order to widen the scope of solid-phase chemistry
there is a constant need for the development of new linker
entities connecting the support material with the starting
material, intermediates, or the envisaged product. Salient
features of such linkers should include robustness towards
a wide range of chemical conditions as well as orthogonal
deprotection procedures.
Scheme 1. Cu++-assisted methanolysis of bpa linker 1; X = Cl, OTf.
Recently, we developed a new amide linker based on bis-
picolylamide (bpa) cleaved by complexation of Cu++ under
very mild conditions.[1] The basis of the cleavage is the
Results and Discussion
We were wondering whether such a principle could also
weakening of the amide bonds in bispicolylamides as a re- be realized for a tetradentate ligand and if so, whether the
sult of the unusual involvement of the amide nitrogen in cleavage conditions would be influenced by an additional
complexation. Methanolysis leads then directly to the coordination site.
methyl ester (Scheme 1). The linker turned out to be very
As reported by Alsfasser, bpa complexes involving an
robust and allowed its application to a wide range of chemi- amide bond are moderately stable and tend to dissociate in
cal conditions. It turned out to be stable under acidic and solution.[2] An additional nitrogen atom for complexation
basic conditions and we have tested its utility for peptide should lead to a more stable complex and as a consequence
to a more pronounced weakening of the amide bond al-
lowing, even milder conditions, amide bond cleavage.
Our first focus was on circular ligand 10, in which a fur-
ther stabilization was expected due to the macrocyclic ef-
fect.[3] A cyclization strategy for peptides with a tetracoor-
[a] Institut für Organische Chemie und Biochemie, Albert-Lud-
wigs-Universität Freiburg,
Albertstrasse 21, 79104 Freiburg, Germany
Fax: +49-761-203-8705
E-mail: willi.bannwarth@organik.chemie.uni-freiburg.de
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Scheme 2. Synthesis route for cyclic tetradentate ligand 10. Reagents and conditions: (a) ethyl trifluoroacetate (3.6 equiv.), H2O
(1.2 equiv.), CH3CN, reflux, 4 h, 97%; (b) Boc2O (1.1 equiv.), NEt3 (3.2 equiv.), THF, 0 °C Ǟ room temp., overnight, 82%; (c) NaOH
(0.2  in MeOH, 2.8 equiv.), MeOH, 0 °C Ǟ room temp., overnight, 73%; (d) 2-nitrobenzenesulfonylchloride (2.0 equiv.), NEt3
(2.0 equiv.), CH2Cl2, overnight, 80%; (e) 2,6-bis(bromomethyl)pyridine (1.3 equiv.), Na2CO3 (5.2 equiv.), DMF, room temp., overnight,
87%; (f) thiophenol (3.3 equiv.), Na2CO3 (10.2 equiv.), DMF, room temp., overnight, 77%; (g) NaH (2.2 equiv.), MeI (2.4 equiv.), DMF,
0 °C Ǟ room temp., overnight, 0%; (h) propionaldehyde (2.0 equiv.), NaBH(OAc)3 (2.8 equiv.), 1,2-DCE, room temp., overnight, 37%;
(i) 1-bromopropane (2.2 equiv.), DIEA (3.0 equiv.), CH3CN, 70 °C, 2 h, 69%; (j) TFA/CH2Cl2 (1:1), iPr3SiH (3.1 equiv.), room temp.,
overnight, quantitative.
dinate Cu++ has been reported.[4] The synthetic route for amine (DIEA) afforded desired product 9b in a yield of
the preparation of cyclic tetradentate ligand 10 is depicted 69%.[9] Final removal of the Boc group by TFA/CH2Cl2
in Scheme 2.
(1:1) with triisopropylsilane as scavenger gave 10 as the
Its synthesis started with the protection of the primary TFA salt in quantitative yield.
amino groups of 2 with ethyl trifluoroacetate in the pres-
ence of water. During this procedure, overreaction was derivatives 13 and 14 by acylation with acyl chlorides 11
avoided by preferential protonation of the secondary and 12 in the presence of NEt3 as outlined in Scheme 3.
amine,[5] leading to compound 3 in nearly quantitative yield
(97%).
Tetradentate ligand 10 was then transformed into acyl
The Boc protection of trifluoroacetate (TFA) salt 3 pro-
ceeded in a yield of 82%. Afterwards, the trifluoroacetyl
groups were removed with a methanolic NaOH solution
(73%) and the final nosyl protection leading to 6 proceeded
in an isolated yield of 80%.
The key step for the synthesis of 10 was the macrocycli-
zation based on the method of Richman and Atkins.[6] By
applying this approach, it was not necessary to work under
high dilution. Dropwise addition of a solution of 2,6-bis-
(bromomethyl)pyridine in DMF over 5 h to a suspension
Scheme 3. Acylation of cyclic ligand 10 with carbonic acid chlo-
rides 11 and 12.
Attempts to cleave the amide bonds by Cu(OTf)2 in a
of 6 and Na2CO3 in DMF resulted in protected macrocycle 300-fold excess of MeOH at room temperature were to no
7 after column chromatography in a yield of 87%. The de- avail. Higher temperatures and other Cu++ sources [CuCl2,
protection of the nosyl protecting group was achieved by Cu(ClO4)2] resulted in no improvement of the situation.
thiolysis with thiophenol in a yield of 77%.
Alsfasser observed by X-ray analysis, UV spectroscopy,
Alkylation with methyl iodide and NaH as base to form and EPR measurements that during methanolysis the bpa
compound 9a led to exhaustive alkylation. Such over-alkyl- copper complex underwent a change in its coordination
ations of the secondary amino groups in azamacrocycles sphere from square pyramidal to a distorted octahedral li-
are already reported in the literature.[7] A reductive amin- gand field, of which the latter was then prone to cleavage
ation with propionaldehyde and sodium triacetoxy borohy- of the amide bond by MeOH.[2] Hence, we surmised that in
dride[8] resulted in desired product 9b although only in a the CuII complexes of 13 and 14 the copper is forced into
moderate yield of 37%. An alternative alkylation with n- a square coordination and not flexible enough to adopt the
propyl bromide in the presence of N,N-diisopropylethyl- required distorted octahedral shape.
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Tetradentate Linker for Amides To be Cleaved by Complexation
Scheme 4. Synthesis of Boc-protected tetradentate linker 22. Reagents and conditions: (a) I2 (1.0 equiv.), tBuI (0.4 equiv.), TFA
(3.0 equiv.), DMSO, 120 °C, 3 h, 65%; (b) N-Boc-ethylenediamine (1.0 equiv.), NaBH(OAc)3 (1.4 equiv.), 1,2-DCE, 1 h, 73%; (c) 1-
propylbromide (5.0 equiv.), DIEA (6.0 equiv.), CH3CN, 70 °C, 15 h, 75%; (d) iPr3SiH (3.0 equiv.), TFA/CH2Cl2 (1:1), 2 h, 100%; (e)
pyridine-2-carboxaldehyde (1.0 equiv.), NaBH(OAc)3 (1.4 equiv.), 1,2-DCE, 1 h; (f) Boc2O (1.3 equiv.), NEt3 (1.4 equiv.), CH2Cl2, 0 °C
Ǟ room temp., 2 h, 76% over two steps; (g) NaOH (1.1 equiv.), MeOH/H2O, reflux, 2 h, 90%.
As a consequence, the more flexible linear tetradentate 21 in 76% yield over the two steps. Saponification with so-
ligand 22 was synthesized (Scheme 4), which after cleavage dium hydroxide in methanol/water resulted then in carbox-
of the Boc group should allow attachment of carboxylic ylic acid 22 in 90% isolated yield.
acids through amide bonds.
Tetradentate units 22 and 23 (which were synthesized ac-
Its synthesis started with the oxidation of commercially cording to Scheme 4, starting with pyridine-2-carboxal-
available methyl 6-methylnicotinate (15) to corresponding dehyde) were then first tested in solution according to
aldehyde 16, which proceeded in a yield of 65%.[10] Re-
ductive amination with N-Boc-ethylenediamine and sodium
triacetoxyborohydride in 1,2-dichloroethane (DCE) gave
secondary amine 17 in a yield of 73%.[7] This was trans-
formed into compound 18 in 75% yield by alkylation with
1-bromopropane and DIEA in CH3CN. Boc deprotection
with TFA/CH2Cl2 (1:1) to free amine 19 was followed by
reductive amination with pyridine-2-carboxaldehyde under
the conditions that were applied to the first reductive amin-
ation procedure. Resulting secondary amine 20 was directly
treated with Boc2O to yield N-Boc-protected methyl ester
Scheme 7. Methanolysis reactions of an aromatic amide bond with
tetradentate construct 27 and tridentate construct 28.
Scheme 5. Boc deprotection, coupling of benzoyl chloride, and sub-
sequent methanolysis of tetradentate ligands 22 and 23. Reagents
and conditions: (a) iPrSiH (3.0 equiv.), TFA/CH2Cl2 (1:1), 2 h; (b)
benzoyl chloride (2.5 equiv.), NEt3 (2.5 equiv.), CH2Cl2, 0 °C Ǟ
room temp., 15 h; (c) Cu(OTf)2 (1.0 equiv.), MeOH, room temp.,
15 h, 55%.
Scheme 6. Coupling of 22 to the solid support and cleavage of the
Boc group. Reagents and conditions: (a) HypoGel400-NH2, DMF,
10 min, then 22 (1.3 equiv.), TBTU (1.3 equiv.), DIEA (8.0 equiv.),
DMF, room temp., 8 h; (b) iPr3SiH (3.0 equiv.), TFA/CH2Cl2 (1:1),
Figure 1. Kinetic data for the methanolysis of an aromatic amide
2 h.
bond with tetradentate construct 27 and tridentate construct 28.
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Scheme 5. After cleavage of the Boc group, benzoyl chloride methyluronium tetrafluoroborate (TBTU) as coupling rea-
was coupled to the free amino function. Exposure to Cu- gent.[11] A negative Kaiser test[12] indicated completion of
(OTf)2 in MeOH for 20 h at room temperature led, to our the coupling reaction after 8 h. Deprotection of the Boc
great satisfaction, to complete cleavage of the amide bond group from 25 yielded 26 (Scheme 6) ready for the attach-
with release of methyl benzoate (24). Without Cu++ no re- ment of substrates through the amide bond.
lease was observed. This experiment indicated at the same
time that the carboxyl function had no influence on the of the C–N bond cleavage of the original tridentate bpa
cleavage conditions. linker with that of the new open-chain tetradentate linker.
This now gave us the possibility to compare the kinetics
After this successful preliminary experiment, Boc-pro- For this reason, benzoyl chloride was coupled to both link-
tected linker 22 was coupled to the amino-functionalized ers and resulting constructs 27 and 28 (Scheme 7) were then
solid support (HypoGel400-NH2) by applying a 1.3 molar subjected to Cu(OTf)2 in MeOH with phenol as the internal
excess and by using O-benzotriazol-1-yl-N,N,NЈ,NЈ-tetra- standard. Aliquots were taken after appropriate time inter-
Scheme 8. Methanolysis reactions of an aliphatic amide bond with
tetradentate construct 29 and tridentate construct 30.
Figure 2. Kinetic data for the methanolysis of an aliphatic amide
bond with tetradentate construct 29 and tridentate construct 30.
Scheme 9. Recycling of the linker. Reagents and conditions: (a) iPr3SiH (3.0 equiv.), TFA/CH2Cl2 (1:1), 2 h; (b) Boc-Ala-OH (3.0 equiv.),
TBTU (3.0 equiv.), DIEA (8.0 equiv.), DMF, room temp., 12 h; (c) Cu(OTf)2 (1.0 equiv.), MeOH, room temp., 15 h, 60%; (d) KCN
(3.0 equiv.), MeOH, room temp., 30 min; (e) Boc-Phe-OH (3.0 equiv.), TBTU, (3.0 equiv.), DIEA (8.0 equiv.), DMF, room temp., 12 h;
(f) Cu(OTf)2 (1.0 equiv.), MeOH, room temp., 15 h, 55%.
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Tetradentate Linker for Amides To be Cleaved by Complexation
vals and analyzed by HPLC with respect to formed methyl- the RCM by employing 5 mol-% of Grubbs II catalyst in
benzoate (24). The kinetic data are depicted in Figure 1.
DCM. Methanolysis after Cu++ complexation yielded de-
As can be deduced from these data the cleavage from sired methyl ester 41 in a yield of 36%.
tetradentate construct 27 occurred to our delight smoothly
and the rate of cleavage was higher than the one from tri-
dentate linker construct 28.
To test whether there is a difference in the cleavage rate
of an aromatic amide and an aliphatic amide, the same ex-
periment was repeated after coupling 4-(4-nitrophenyl)-
butyric acid to the tridentate and tetradentate linkers
(Scheme 8). Here it turned out, that the cleavage rate was
slower on both linkers, but proceeded faster on the tetra-
dentate linker system (Figure 2).
Although the new tetradentate linker can be synthesized
in a straightforward way, its recyclability is still of concern.
For this, the Boc group from 25 was cleaved, which was
followed by coupling of Boc-Ala-OH leading to 32 using
the standard coupling protocol outlined in Scheme 9. After
12 h a chloranil test indicated complete attachment.[13]
Equimolar amounts of Cu(OTf)2 in MeOH led to the re-
lease of Boc-Ala methyl ester 33 in an isolated yield of 60%
over the three steps. Decomplexation to 26 was achieved by
treatment with a methanolic solution of KCN (3 equiv.)
over 30 min, whereby the resin lost its green color.
To regenerated linker 26 was coupled Boc-Phe-OH, and
the release was again performed with Cu(OTf)2 in MeOH,
which resulted in pure Boc-Phe methyl ester 35 in a yield
of 55% and without any trace of Boc-Ala methyl ester 33,
indicating that the first release had proceeded quantita-
tively.
A critical issue for a linker system is its robustness, which
is closely related to its compatibility with as many reaction
conditions as possible. This will eventually determine its
scope of application. Therefore, our next activities were di-
rected towards this topic.
The new linker system turned out to be stable under
acidic (50% TFA in DCM) and basic conditions (0.2 
LiOH in water) as well as in the presence of fluoride ions
(0.1  Bu4NF in THF). To demonstrate the scope of appli-
Scheme 10. Scope of reactions performed with the new open-chain
cations of the new linker system the reactions depicted in tetradentate linker. Reagents and conditions: Reductive amination
(A): (a) 4-carboxybenzaldehyde (3.0 equiv.), TBTU (3.0 equiv.),
DIEA (8.0 equiv.), DMF, room temp., 12 h; (b) piperidine
Scheme 10 (A–G) were carried out.
Reaction A comprises a reductive amination, in which 4-
(10 equiv.), NaBH(OAc)3 (10 equiv.), 1,2-DCE, room temp., 12 h;
carboxybenzaldehyde was coupled to linker 26 after Boc
(c) Cu(OTf)2 (1.0 equiv.), MeOH, room temp., 15 h, 51%; Suzuki–
deprotection from linker 25, resulting in 36. This was fol-
lowed by reductive amination with sodium triacet-
oxyborohydride in DCE. Methanolysis after complexation
with Cu++ gave desired methyl ester 37 in a yield of 51%
over the four steps (Boc deprotection, attachment of the
Miyaura coupling (B): (d) 4-iodobenzoic acid (3.0 equiv.), TBTU
(3.0 equiv.), DIEA (8.0 equiv.), DMF, room temp., 12 h; (e)
PhB(OH)2 (5.0 equiv.), K3PO4 (10 equiv.), Pd(PPh3)4 (10 mol-%),
DMF, 90 °C, 12 h, 48%; ring-closing metathesis (C): (f) 2-allyl-4-
pentenoic acid (3.0 equiv.), TBTU (3.0 equiv.) DIEA (8.0 equiv.),
DMF, room temp., 12 h; (g) Grubbs 2nd generation catalyst (5 mol-
acid, reductive amination, and release by methanolysis) and %), CH2Cl2, room temp., 24 h, 36%; Heck reaction (D): (h) acrylic
acid ethyl ester (3.0 equiv.), Pd(OAc)2 (10 mol-%), PPh3
based on the original functionalization of the support.
(0.3 equiv.), K2CO3 (5.0 equiv.), NBu4Cl (1.0 equiv.), toluene,
In reaction B 4-iodobenzoic acid was first coupled to
80 °C, 4 d, 55%; Horner–Wadsworth–Emmons reaction (E): (i) di-
linker 26 to yield 38 and then a Suzuki–Miyaura coupling
ethoxyphosphorylacetic acid methyl ester (3.0 equiv.), nBuLi
was performed with phenylboronic acid by using Pd-
(PPh3)4 as catalyst. Final methyl ester 39 was obtained in a
yield of 48%.
In reaction C a ring-closing metathesis (RCM) reaction
was carried out by attaching first 2-allyl-4-pentenoic acid
(3.0 equiv.), THF, 0 Ǟ –78 °C, 3.5 h, 51%; Mitsunobu reaction (F):
(j) 4-(tert-butyldimethylsilanyloxy)benzoic acid (3.0 equiv.), TBTU
(3.0 equiv.), DIEA (8.0 equiv.), DMF, room temp., 12 h; (k)
Cs2CO3 (3.0 equiv.), DMF/H2O (10:1), room temp., 2 h; (l) allyl
alcohol (4.5 equiv.), DIAD (4.8 equiv.), PPh3 (3.6 equiv.), CH2Cl2,
room temp., 20 h, 72%; Grignard reaction (G): (m) vinylmagne-
to the linker, and resulting 40 was used as a substrate for sium chloride (5.0 equiv.), THF, 0 °C Ǟ room temp., 15 h, 60%.
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Reaction D was a Heck reaction with 4-iodobenzoic acid volving click chemistry, which is so rampant these days. In
coupled to linker 38 as a starting point. The reaction was the first reaction sequence (Scheme 11), Fmoc-Phe-OH was
carried out in toluene under an atmosphere of argon by coupled to linker 26, which in turn had been obtained after
using Pd(OAc)2/PPh3 as catalyst and an excess amount of cleavage of the Boc group from 25. This was followed by
ethyl acrylate in the presence of K2CO3. Final methyl ester cleavage of the Fmoc group with 20% piperidine in DMF.
42 was obtained in a yield of 55%.
A diazo transfer with the use of triflic azide[14] and a cata-
For the Horner–Wadsworth–Emmons reaction (reac- lytic amount of CuSO4·5H2O led to quantitative azide for-
tion E), 36 was treated with a solution of nBuLi and di- mation, which was proven by a negative Kaiser test. For
ethoxyphosphorylacetic acid methyl ester in THF at –78 °C. this diazo transfer a small amount of MeOH was added to
After Cu++ complexation and methanolysis, methyl ester 43 the reaction mixture to enhance the solubility of CuSO4,
could be isolated in a yield of 51%.
although this might have caused a minute amount of
For the envisaged Mitsunobu reaction (reaction F) TBS- premature cleavage by methanolysis. To the azide was
protected p-hydroxybenzoic acid was first coupled to 26, added an excess amount of phenylacetylene and catalytic
yielding intermediate 44. After deprotection of the TBS amounts of -(+)-ascorbic acid and CuSO4·5H2O in DMF.
group with Cs2CO3 in DMF/H2O (10:1) at room tempera- After agitation for 20 h at room temperature and several
ture for 2 h the Mitsunobu condensation was carried out washing steps, subsequent methanolysis after Cu++ com-
with allyl alcohol in the presence of DIAD and PPh3 in plexation yielded methyl ester 47 in an overall yield of 53%
DCM. Methanolysis after Cu++ complexation led to the de- as a single product in pure form (determined by HPLC
sired product in a yield of 72% over the five steps (Boc analysis). This high yield over seven steps (starting from
deprotection, attachment of the acid, TMS deprotection, Hypogel400-NH2) implies an individual yield per step of
Mitsunobu condensation, methanolysis).
over 90%, which indicates that, if at all, only a small
Finally, a Grignard reaction (reaction G) was performed amount was cleaved prematurely during the diazo transfer
starting from 36 by adding vinylmagnesium chloride in reaction.
THF dropwise at 0 °C. Desired methyl ester 46 was ob-
In the alternative sequence, p-iodobenzoic acid was first
tained in a yield of 60%.
attached to support 26. This was followed by a Sonogashira
In addition to the examples illustrated in Scheme 10 two reaction employing ethinyltrimethylsilane and catalytic
reaction sequences on the linker system were performed in-
Scheme 12. Sonogashira reaction, TMS deprotection, and click re-
Scheme 11. Diazo transfer and click reaction. Reagents and condi-
tions: (a) Fmoc-Phe-OH (3.0 equiv.), TBTU (3.0 equiv.), DIEA
(8.0 equiv.) room temp., 12 h; (b) piperidine/DMF (2:8, 2ϫ4 mL,
5 min); (c) triflic azide solution in pyridine (18 equiv.),
action. Reagents and conditions: (a) p-iodobenzoic acid
(3.0 equiv.), TBTU (3.0 equiv.), DIEA (8.0 equiv.), DMF, room
temp., 12 h; (b) ethinyltrimethylsilane (2.0 equiv.), PdCl2(PPh3)2
(5 mol-%), CuI (10 mol-%), PPh3 (0.2 equiv.), DMF/NEt3 (2:1),
CuSO4·5H2O (10 mol-%), MeOH (10% v/v), room temp., 20 h; (d) 80 °C, 24 h; (c) TBAF·3H2O (1.2 equiv.), THF, room temp., 24 h;
phenylacetylene (2.0 equiv.), -(+)-ascorbic acid (0.1 equiv.), (d) benzyl azide (2.0 equiv.), -(+)-ascorbic acid (0.1 equiv.),
CuSO4·5H2O (2 mol-%), DMF, room temp., 24 h; (e) Cu(OTf)2 CuSO4·5H2O (2 mol-%), DMF, room temp., 24 h; (e) Cu(OTf)2
(1.0 equiv.), MeOH, room temp., 15 h, 53% over seven steps. (1.0 equiv.), MeOH, room temp., 15 h, 41% over seven steps.
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Tetradentate Linker for Amides To be Cleaved by Complexation
General Procedure for Cu++-Assisted Cleavage of the Linker Sys-
tems: The corresponding solid support was suspended in MeOH
(3 mL). After 10 min, a solution of Cu(OTf)2 (1.0 equiv.) in MeOH
(2 mL) was added. The mixture was agitated for 15 h at room tem-
perature. The solid support was filtered off, and the methanolic
solution was evaporated. The residue was taken up in CH2Cl2
(5 mL) and extracted with aqueous EDTA solution (0.5 ,
2ϫ10 mL) and H2O (10 mL). The organic layer was dried with
Na2SO4 and evaporated to yield the corresponding methyl ester.
amounts of PdCl2(PPh3)2, CuI, and PPh3 in DMF/NEt3
(2:1) at 80 °C (Scheme 12). The TMS protecting group was
cleaved with TBAF in THF, and the resulting alkyne was
converted into the triazole through a click reaction with an
excess amount of benzyl azide and catalytic amounts of -
(+)-ascorbic acid and CuSO4·5H2O in DMF. Methanolysis
after Cu++ complexation gave methyl ester 48 in an overall
yield of 41% yield as determined by HPLC.
General Procedure for Copper Decomplexation of the Tri- and Tetra-
dentate Linker: The corresponding solid support was suspended in
MeOH (3 mL). After 10 min, a solution of KCN (3.0 equiv.) in
MeOH (2 mL) was added. The mixture was agitated at room tem-
perature for 30 min. The solid support was filtered and washed
with H2O (3ϫ5 mL), DMF (3ϫ5 mL), MeOH (3ϫ5 mL),
CH2Cl2 (3ϫ5 mL), and Et2O (3ϫ5 mL).
Conclusions
We have demonstrated that the concept of weakening
amide bonds by forced complexation of the nitrogen to
Cu++ is not limited to tridentate ligands but can be ex-
tended to tetradentate ligands. A prerequisite is obviously a
certain flexible arrangement of the coordination sites, which
cannot be achieved by cyclic tetradentate ligands. An open-
chain tetradentate ligand allowed mild cleavage of amides
by methanolysis after complexation. The principle was used
for the development of a new linker for solid-phase chemis-
try, and comparison with our previously published triden-
tate ligand revealed that cleavage of amides was faster by
applying the new system.
Bis[3-(2,2,2-trifluoroacetamido)propyl]ammonium 2,2,2-Trifluoro-
acetate (3): A solution of N,N-bis(3-aminopropyl)amine (2; 3.0 mL,
21 mmol) and ethyl trifluoroacetate (9.0 mL, 76 mmol, 3.6 equiv.)
in CH3CN (60 mL) and H2O (0.5 mL) was heated at reflux for 4 h.
After cooling to room temperature the product precipitated as a
white solid (7.9 g, 18 mmol, 85%). From the mother liquor ad-
ditional product 3 could be obtained by partial evaporation (1.1 g,
2.5 mmol, 12%). Overall yield: 9.0 g (20.5 mmol, 97%; ref.[15]
1
97%). M.p. 173–174 °C (ref.[15] 120–121 °C). H NMR (400 MHz,
[D6]acetone): δ = 2.12 (tt, J = 9.6, 9.4 Hz, 4 H, 2ϫNH2-CH2-
CH2-), 3.26 (t, J = 9.6 Hz, 4 H, 2ϫNH-CH2-), 3.49 (mc, 4 H,
2ϫNH2-CH2-), 8.95 (br. s, 2 H, -NH2+-), 9.32 (br. s, 2 H, 2ϫ
NH-) ppm. 13C NMR (100 MHz, [D6]acetone): δ = 26.2, 37.3, 46.1,
117.0 (q, JC,F = 287 Hz), 118.0 (q, JC,F = 294 Hz), 158.0 (q, JC,F
= 37 Hz), 161.9 (q, JC,F = 34 Hz) ppm. MS (CI, NH3): m/z (%) =
325.1 (13) [M + 1]+, 324.1 (100) [M]+, 183.0 (11).
The linker was synthesized in a straightforward manner
and we also demonstrated its recyclability. Besides that, the
linker turned out to be very robust. It is stable towards ba-
sic and acidic conditions and its versatility was demon-
strated by its compatibility with a whole myriad of different
types of reactions. The demonstrated examples are by no
means exhausted and we are confident that the generality
of the concept will stimulate further applications.
tert-Butyl Bis[3-(2,2,2-trifluoroacetamido)propyl]carbamate (4): To
a suspension of TFA salt 3 (4.0 g, 9.1 mmol, 1.0 equiv.) in NEt3
(4.0 mL, 29 mmol, 3.2 equiv.) was added a solution of Boc2O
(2.4 mL, 10 mmol, 1.1 equiv.) in THF (10 mL) dropwise at 0 °C.
The solution was stirred at room temperature overnight, and the
reaction was terminated by the addition of H2O (100 mL). The
aqueous phase was extracted with ethyl acetate (EE) (3ϫ100 mL),
the combined organic layer was dried with Na2SO4, and the sol-
vents were evaporated. Recrystallization from Et2O/n-hexane gave
product 4 as a white solid (3.1 g, 7.4 mmol, 82%; ref.[15] 90%). The
spectroscopic data are in accordance to those reported in litera-
ture.[16]
Experimental Section
General: All reactions with air- and moisture-sensitive compounds
were carried out under an argon atmosphere. All solvents were ana-
lytical grade or better. Dry CH2Cl2 was distilled from CaH2. 1H
NMR and 13C NMR spectra were recorded with a Bruker AM 400
spectrometer with Me4Si as internal reference. Mass spectrometry
was carried out with a Finnigan MAT312 spectrometer by using
chemical ionization (CI) method and a Finnigan MAT8200 spec-
trometer by using electrospray ionization (ESI) method. Elemental
analyses were measured with an Elementar Vario EL (Elementar
Analysesysteme GmbH). For column chromatography, Merck sil-
ica gel 60 (40–63 µm) was used. The progress of the reactions was
checked on TLC plates (silica gel 60, F-254, Merck). HPLC analy-
sis was performed with an Agilent 1100 Series HPLC system. An
Agilent Zorbax Eclipse 4.6ϫ150 mm XDB-C8 column was used
with a flow rate of 1 mLmin–1 and a H2O/CH3CN gradient (70:30
Ǟ 30:70).
tert-Butyl Bis(3-aminopropyl)carbamate (5): To a solution of pro-
tected triamine 4 (1.95 g, 4.69 mmol, 1.0 equiv.) in MeOH (60 mL)
was added a solution of NaOH (0.2  in MeOH, 65 mL, 13 mmol,
2.8 equiv.) was added dropwise at 0 °C. The solution was stirred at
room temperature overnight, and the solvent was removed under
reduced pressure. The residue was dissolved in H2O (20 mL) and
extracted with MeOH/CHCl3 (9:1, 3ϫ30 mL). The combined or-
ganic layer was dried with Na2SO4 and concentrated under reduced
pressure to yield 5 (790 mg, 3.42 mmol, 73%; ref.[15] 97%). as a
colorless oil. The spectroscopic data are in accordance to those
reported in literature.[16]
General Procedure for Coupling of Carboxylic Acids to Linker 26:
The solid phase carrying linker 25 (300 mg, 0.163 mmol) was sus-
pended in DMF (2 mL). After 10 min, a solution of the corre-
sponding acid (3.0 equiv.), TBTU (157.0 mg, 0.489 mmol
3.0 equiv.) and DIEA (0.223 mL, 1.30 mmol, 8.0 equiv.) in DMF
(3 mL) was added. The mixture was agitated at room temperature
for 12 h. The solid support was filtered and washed alternately with
DMF/iPrOH (5ϫ3 mL) and subsequently with CH2Cl2 (3 mL)
and Et2O (3 mL).
tert-Butyl Bis[3-(2-nitrophenylsulfonamido)propyl]carbamate (6): To
a solution of mono Boc-protected triamine 5 (59 mg, 0.26 mmol,
1.0 equiv.) and NEt3 (72 µL, 0.51 mmol, 2.0 equiv.) in CH2Cl2
(2 mL) was added dropwise at room temperature a solution of 2-
nitrobenzoylsulfonyl chloride (113 mg, 0.51 mmol, 2.0 equiv.) in
CH2Cl2 (2 mL). The solution was stirred overnight, and the reac-
tion was terminated by the addition of H2O (10 mL). The aqueous
Eur. J. Org. Chem. 2009, 4273–4283
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4279

R. A. Kramer, M. C. Bröhmer, N. V. Forkel, W. Bannwarth
FULL PAPER
phase was extracted with CH2Cl2 (2ϫ10 mL), the combined or-
ganic layer was dried with Na2SO4, and the solvents were evapo-
rated. Column chromatography (CH2Cl2/MeOH, 98:2) gave title
compound 6 as a white foam (126 mg, 0.21 mmol, 80%). 1H NMR
was redissolved in CH2Cl2 (10 mL), the organic phase was washed
with H2O (10 mL), and the aqueous phase was extracted with
CHCl3 (3ϫ10 mL). The combined organic layer was dried with
Na2SO4, and the solvents were evaporated. Column chromatog-
(300 MHz, CDCl3): δ = 1.42 (s, 9 H, -OtBu), 1.70 (dd, J = 6.6, raphy (CH2Cl2/MeOH, 90:10) gave title compound 9b as a yellow
1
6.3 Hz, 4 H, 2ϫNHBoc-CH2-CH2-), 3.08 (mc, 4 H, 2ϫNHBoc- resin (85 mg, 0.20 mmol, 69%). H NMR (300 MHz, CDCl3): δ =
CH2-), 3.22 (t, J = 6.6 Hz, 4 H, 2ϫNHBoc-CH2-CH2-CH2-), 7.70–
7.78 (m, 4 H, Harom.), 7.80–7.88 (m, 2 H, Harom.), 8.08–8.16 (m, 2
H, Harom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.4, 28.3, 41.1,
46.1, 80.5, 125.3, 130.9, 132.7, 133.6 (2 overlayed signals), 148.0,
0.90 (t, J = 7.3 Hz, 2ϫ-CH2CH2CH3), 1.32 (s, 9 H, -OtBu), 1.52–
1.76 (m, 8 H, 2ϫ-CH2CH2CH3, 2ϫNHBoc-CH2-CH2-), 2.52 (t,
J = 7.0 Hz, 4 H, 2ϫNHBoc-CH2-CH2-CH2-), 2.61 (t, J = 7.5 Hz,
4 H , 2 ϫ N H B o c C H 2 - ) , 3 . 1 0 ( t , J = 6 . 3 Hz , 4 H, 2 ϫ
156.1 ppm. MS (CI, NH3): m/z (%) = 502.2 (100) [M + 1 – Boc]+. -CH2CH2CH3), 3.79 (s, 4 H, 2ϫpy-CH2-), 7.22 [d, J = 7.6 Hz, 2
H, C(3,5) of pyridine], 7.58 [t, J = 7.6 Hz, C(4) of pyridine] ppm.
3,11-Bis(2-nitrobenzenesulfonyl)-7-tert-butyloxycarbonyl-3,7,11,17-
MS (EI): m/z (%) = 419.2 (8) [M + 1]+, 418.1 (31) [M]+, 322.1 (11),
tetraazabicyclo[11.3.1]heptadeca-1(16),13(17),14-triene (7): A sus-
321.1 (58), 221.1 (11), 163.1 (15), 159.0 (11), 148.0 (21), 133.0 (10),
127.1 (14), 107.0 (100), 106.0 (42), 98.0 (70), 86.0 (16), 70.0 (11),
57.0 (23), 41.0 (16).
pension of protected triamine 6 (3.24 g, 5.38 mmol, 1.0 equiv.) and
Na2CO3 (2.97 g, 28.0 mmol, 5.2 equiv.) in DMF (140 mL) was
stirred at room temperature for 1.5 h, followed by the addition of
a solution of 2,6-bis(bromomethyl)pyridine (1.85 g, 6.99 mmol,
1.3 equiv.) in DMF (140 mL) over a period of 5 h. The resulting
solution was stirred at room temperature overnight, DMF was re-
moved by recondensation, and the residue was redissolved in
CH2Cl2 (250 mL). The organic phase was washed with NaOH
(0.1 , 2ϫ100 mL), dried with Na2SO4, and evaporated under re-
duced pressure. Column chromatography [cyclohexane (CH)/EE,
60:40 Ǟ 0:100] gave title compound 7 as a white foam (3.30 g,
3,11-Bispropyl-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-
1(16),13(17),14-triene 2,2,2-Trifluoroacetate (10): A solution of
Boc-protected tetraazamacrocycle 9b (60 mg, 0.14 mmol,
1.0 equiv.) and iPr3SiH (88 µL, 0.43 mmol, 3.1 equiv.) in CH2Cl2/
TFA (1:1, 3 mL) was stirred at room temperature overnight. The
solvent was removed under reduced pressure, and the crude prod-
uct was purified by column chromatography (CH2Cl2/MeOH,
90:10 Ǟ 85:15) to give title compound 10 as a yellow oil (61 mg,
1
1
4.68 mmol, 87%). H NMR (300 MHz, CDCl3): δ = 1.37 (s, 9 H,
0.14 mmol, 100%). H NMR (400 MHz, MeOD): δ = 0.92 (t, J =
-OtBu), 1.61 (mc, 4 H, 2ϫNHBoc-CH2-CH2-) 3.07 (t, J = 6.2 Hz, 7.4 Hz, 6 H, 2ϫ-CH2CH2CH3), 1.70 (qt, J = 7.8, 7.4 Hz, 4 H, 2ϫ
4 H, 2ϫNHBoc-CH2-), 3.26 (t, J = 7.5 Hz, 4 H, 2ϫNHBoc-CH2- -CH2CH2CH3), 2.24 (tt, J = 5.3, 2.7 Hz, 4 H, 2ϫNHBoc-CH2-
CH2-CH2-), 7.56 (br. d, J = 7.5 Hz, 2 H, Harom.), 7.64–7.82 (m, 7 CH2-), 2.81 (mc, 4 H), 3.24–3.31 (m, 8 H), 4.26 (s, 4 H, 2ϫpy-
H, Harom.), 8.03–8.08 (m, 2 H, Harom.) ppm. 13C NMR (100 MHz, CH2-), 7.52 [d, J = 7.7 Hz, 2 H, C(3,5) of pyridine], 7.91 [t, J =
CDCl3): δ = 28.3, 28.7, 46.8, 47.5, 54.1, 79.8, 123.8, 124.3 (2 over-
layed signals), 130.7, 131.0, 131.8, 132.8, 133.7, 148.2, 155.5 ppm.
MS (ESI+): m/z (%) = 727.2 (100) [M + Na]+, 704.9 (12) [M]+,
7.7 Hz, 1 H, C(4) of pyridine] ppm. 13C NMR (100 MHz, MeOD):
δ = 11.5, 19.4, 22.0, 49.3, 52.1, 56.6, 57.5, 118.2 (q, JC,F = 293 Hz),
126.5, 140.2, 155.0, 163.0 (q, JC,F = 34 Hz) ppm. MS (ESI+): m/z
648.9 (17), 627.2 (21), 606.2 (12), 605.2 (43). C30H36N6O10S2 (%) = 319.2 (100) [M + 1]+, 234.2 (6), 114.7 (8).
(704.77): calcd. C 51.51, H 5.41, N 11.28, S 8.70; found C 51.13,
3,11-Bispropyl-7-benzoyl-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-
H 5.15, N 11.92, S 9.10.
1(16),13(17),14-triene (13): To a solution of benzoyl chloride (11;
23 µL, 0.19 mmol, 2.5 equiv.) in CH2Cl2 (1 mL) was added at 0 °C
a solution of tetraazamacrocycle 10 (33 mg, 0.076 mmol, 1.0 equiv.)
and NEt3 (28 µL, 0.19 mmol, 2.5 equiv.) in CH2Cl2 (1.5 mL). The
solution was stirred at room temperature overnight. The organic
phase was washed with H2O (2ϫ3 mL), dried with Na2SO4, and
the solvents were evaporated. Column chromatography (CH2Cl2/
MeOH, 95:5 Ǟ 90:10) gave title compound 13 as a yellow resin
7-tert-Butyloxycarbonyl-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-
1(16),13(17),14-triene (8): To a suspension of ternary protected tet-
raazamacrocycle 7 (3.30 g, 4.70 mmol, 1.0 equiv.) and Na2CO3
(5.10 g, 48.0 mmol, 10.2 equiv.) in DMF (200 mL) was added drop-
wise thiophenol (1.70 g, 15.5 mmol, 3.3 equiv.). The solution was
stirred at room temperature overnight. DMF was removed by re-
condensation, and the residue was redissolved in CH2Cl2 (250 mL).
The organic phase was washed with H2O (2ϫ100 mL), and the (17 mg, 0.046 mmol, 61%). 1H NMR (300 MHz, CDCl3): δ = 0.88
combined aqueous layer was extracted with CH2Cl2 (2ϫ50 mL).
To obtain a clear solution, MeOH (10 mL) was added to the com-
bined organic layer before they were dried with Na2SO4 and evapo-
rated under reduced pressure. Column chromatography (CH2Cl2 Ǟ
MeOH Ǟ MeOH/25% aq. NH3 95:5) and lyophilization of the
product fractions after evaporation of H2O (10 mL) gave title com-
(t, J = 7.2 Hz, 6 H, 2ϫ-CH2CH2CH3), 1.43–2.10 (m, 8 H), 2.34–
2.91 (m, 8 H), 3.14–3.59 (m, 4 H), 3.73–4.04 (m, 4 H), 7.24–7.32
(m, 7 H), 7.67 [t, J = 7.6 Hz, 1 H, C(4) of pyridine] ppm. MS (EI):
m/z (%) = 423.4 (9) [M + 1]+, 422.4 (32) [M]+, 326.3 (20), 325.5
(100), 259.3 (10), 250.3 (10), 219.2 (16), 164.2 (10), 163.2 (17), 162.1
(30), 107.1 (48), 106.1 (30), 105.1 (63), 98.1 (63), 77.1 (18), 36.0
(11).
1
pound 8 as a yellow resin-like solid (1.21 g, 3.60 mmol, 77%). H
NMR (400 MHz, MeOD): δ = 1.23 (s, 9 H, -OtBu), 1.85 (mc, 4 H,
2 ϫ NHBoc-CH2-CH2-), 2.50 (mc, 4 H, 2 ϫ NHBoc-CH2-CH2-
CH2-), 3.33 (mc, 4 H, 2 ϫ NHBoc-CH2-), 4.04 (s, 4 H, 2 ϫ py-
CH2-), 7.24 [d, J = 7.7 Hz, 2 H, C(3,5) of pyridine], 7.73 [t, J =
7.7 Hz, 1 H, C(4) of pyridine] ppm. 13C NMR (100 MHz, MeOD):
δ = 28.5, 31.6, 46.2, 48.0, 53.5, 80.9, 122.9, 138.8, 157.6, 158.4 ppm.
3,11-Bispropyl-7-(4-methoxyphenyl)acetyl-3,7,11,17-tetraazabicyclo-
[11.3.1]heptadeca-1(16),13(17),14-triene (14): To a solution of 4-
methoxyphenylacetyl chloride (12; 95 µL, 0.61 mmol, 2.5 equiv.) in
CH2Cl2 (3 mL) was added at 0 °C a solution of tetraazamacrocycle
10 (106 mg, 0.245 mmol, 1.0 equiv.) and NEt3 (87 µL, 0.61 mmol,
2.5 equiv.) in CH2Cl2 (1.5 mL). It was stirred at room temperature
overnight. The organic layer was washed with H2O (2 ϫ3 mL),
3,11-Bispropyl-7-tert-butyloxycarbonyl-3,7,11,17-tetraazabicyclo-
[11.3.1]heptadeca-1(16),13(17),14-triene (9b): A solution of Boc- dried with Na2SO4, and the solvents were evaporated. Column
protected tetraazamacrocycle 8 (97 mg, 0.029 mmol, 1.0 equiv.), 1-
brompropane (59 µL, 0.64 mmol, 2.2 equiv.), and DIEA (0.15 mL,
chromatography (CH2Cl2/MeOH, 95:5 Ǟ 90:10) gave title com-
pound 14 as a yellow resin (43 mg, 0.091 mmol, 37%). 1H NMR
0.87 mmol, 3.0 equiv.) in CH3CN (4 mL) was heated to 70 °C for ( 4 0 0 M H z , C D C l 3 ) : δ = 0 . 8 8 ( t , J = 7 . 3 Hz , 6 H, 2 ϫ
2 h. The solvent was removed under reduced pressure. The residue -CH2CH2CH3), 1.49–1.80 (m, 8 H, 2ϫ-CH2CH2CH3, 2ϫNHCO-
4280
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4273–4283

Tetradentate Linker for Amides To be Cleaved by Complexation
CH2-CH2-), 2.44–2.67 (m, 8 H, 2 ϫ -CH2CH2CH3, 2 ϫNHCO-
CH2-CH2-CH2-), 3.19–3.35 (m, 4 H, 2ϫNHCO-CH2-), 3.54 (s, 4
H, 2ϫpy-CH2-), 3.72 (s, 2 H, Ar-CH2-CO-), 3.80 (s, 3 H, -OMe),
18 (0.97 g, 2.8 mmol, 1.0 equiv.) in TFA/CH2Cl2 (1:1, 10 mL) was
added iPr3SiH (1.7 mL, 8.3 mmol, 3.0 equiv.). The mixture was
stirred at room temperature for 2 h, followed by removal of the
6.81 (mc, 2 H, Harom.), 7.09 (mc, 2 H, Harom.), 7.15–7.30 (m, 2 H, solvent under reduced pressure. Column chromatography (CH2Cl2/
H
arom.), 7.59 [t, J = 7.6 Hz, 1 H, C(4) of pyridine] ppm. 13C NMR MeOH, 98:2 Ǟ 90:10) gave title compound 19 as a brown oil
1
(100 MHz, CDCl3): δ = 11.7, 20.0 (2 overlayed signals), 39.6, 44.4,
46.8, 51.5, 55.2, 59.6, 114.0, 123.0, 123.2, 127.5, 129.6, 136.8, 158.3,
171.1 ppm. MS (EI): m/z (%) = 467.4 (100) [M + 1]+, 262.3 (15).
(1.32 g, 2.75 mmol, 100%). H NMR (400 MHz, CDCl3): δ = 0.88
(t, J = 7.3 Hz, 3 H, -CH2-CH3), 1.57–1.82 (m, 2 H, -CH2-CH3),
2.99 (mc, 2 H, -CH2-CH2-CH3), 3.44 [mc, 4 H, -CH2-N(propyl)-
CH2-,-CH2-NH3+], 3.93 (s, 3 H, -CO2Me), 4.33 (s, 2 H, py-CH2-),
7.48 (d, J = 8.2 Hz, 1 H, Harom.), 8.33 (dd, J = 8.1, 2.1 Hz, 1 H,
Harom.), 9.15 (d, J = 2.0 Hz, 1 H, Harom.) ppm. 13C NMR
(100 MHz, CDCl3): δ = 10.9, 18.2, 35.9, 51.7, 52.6, 56.8, 57.1,
116.4, 123.8, 126.2, 138.8, 150.5, 157.0, 165.1 ppm. 19F NMR: δ =
–75.81 ppm. MS (ESI+): m/z (%) = 252.1 (100) [M – 2CF3COO–
H]+.
Methyl 6-Formylnicotinate (16): To a solution of methyl 6-methyl-
nicotinate (15; 2.00 g, 13.2 mmol, 1.0 equiv.) in DMSO (50 mL)
was added iodine (3.35 g, 13.2 mmol, 1.0 equiv.), TFA (3.05 mL,
39.6 mmol, 3.0 equiv.), and tBuI (0.62 mmol, 5.2 mmol, 0.4 equiv.).
The mixture was heated to 120 °C for 3 h. After cooling to room
temperature an aqueous solution of Na2S2O3 (0.1 , 100 mL) and
a solution of NaHCO3 (10%, 120 mL) were added. The aqueous
layer was extracted with CH2Cl2 (4ϫ100 mL), the organic layer
was dried with Na2SO4, and the solvents were evaporated. Column
chromatography (CH2Cl2/MeOH, 98:2) gave title compound 21 as
a brown oil (1.43 g, 8.7 mmol, 65%). The spectroscopic data were
in accordance with those reported in literature.[10]
Methyl 6-({2-[tert-Butoxycarbonyl(pyridine-2-ylmethyl)amino]ethyl-
(propyl)amino}methyl)nicotinate (21): To a solution of methyl ester
19 (1.29 g, 2.69 mmol, 1.0 equiv.) and pyridine-2-carboxaldehyde
(0.256 mL, 2.69 mmol, 1.0 equiv.) in 1,2-DCE (12 mL) was added
NaBH(OAc)3 (0.78 g, 3.77 mmol, 1.4 equiv.). The mixture was
stirred at room temperature for 1.5 h, followed by the addition of
an aqueous solution of NaHCO3 (12 mL). The aqueous layer was
extracted with CH2Cl2 (3ϫ15 mL), the organic layer was dried
with Na2SO4, and the solvents were evaporated to give crude sec-
ondary amine 20 as a brown oil (0.85 g, 2.48 mmol, 92%). To a
solution of crude 20 (0.85 g, 2.48 mmol, 1.0 equiv.) and NEt3
(0.49 mL, 3.52 mmol, 1.4 equiv.) in CH2Cl2 (20 mL) was added
slowly Boc2O (0.70 mL, 3.27 mmol, 1.3 equiv.) at 0 °C. The cooling
bath was removed and the mixture was stirred at room temperature
for 2 h. After addition of H2O (30 mL) the layers were separated,
and the aqueous layer was extracted with CH2Cl2 (3ϫ30 mL). The
combined organic layer was dried with Na2SO4 and the solvents
were evaporated. Column chromatography (CH2Cl2/MeOH, 97:3)
gave title compound 21 as a brown oil (0.84 g, 1.9 mmol, 76%). 1H
NMR (400 MHz, CDCl3): δ = 0.82 (t, J = 7.3 Hz, 3 H, -CH2-CH3),
1.38 (s, 9 H, OtBu), 1.42–1.48 (m, 2 H, -CH2-CH3), 2.42 (mc, 2 H,
-CH2-CH2-CH3), 2.64 [mc, 2 H, -CH2-N(propyl)-CH2], 3.38 (mc, 2
H, -CH2-NBoc-), 3.78 [s, 2 H, py-CH2-N(propyl)-], 4.52 (d, J =
14.8 Hz, 2 H, py-CH2-NBoc-) 3.93 (s, 3 H, -CO2Me), 7.11–7.24 (m,
2 H, Harom.), 7.51–7.65 (m, 2 H, Harom.), 8.21 (d, J = 8.2 Hz, 1 H,
Methyl 6-{[2-(tert-Butoxycarbonylamino)ethylamino]methyl}-
nicotinate (17): To a solution of 16 (1.27 g, 7.69 mmol, 1.0 equiv.)
and N-Boc-ethylenediamine (1.21 mL, 7.69 mmol, 1.0 equiv.) in
1,2-DCE (30 mL) was added NaBH(OAc)3 (2.28 g, 10.8 mmol,
1.4 equiv.). The mixture was stirred at room temperature for 1.5 h.
An aqueous solution of NaHCO3 (30 mL) was added. The aqueous
layer was extracted with CH2Cl2 (3ϫ30 mL), the organic layer was
dried with Na2SO4, and the solvents were evaporated. Column
chromatography (CH2Cl2/MeOH, 98:2 Ǟ 95:5) gave title com-
pound 17 as a brown oil (1.74 g, 5.61 mmol, 73 %). 1H NMR
(400 MHz, CDCl3): δ = 1.42 (s, 9 H, -OtBu), 2.77 (t, J = 5.8 Hz, 2
H, -CH2-NH-CH2-), 3.24 (td, J = 5.8, 5.7 Hz, 2 H, -CH2-NH-Boc),
3.91 (s, 3 H, -CO2Me), 3.96 (s, 2 H, py-CH2-), 5.05 (br. s, 1 H,
-NH-), 7.37 (d, J = 8.1 Hz, 1 H, Harom.), 8.22 (dd, J = 8.0, 2.1 Hz,
1 H, Harom.), 9.13 (br. dd, J = 2.1, 0.6 Hz, 1 H, Harom.) ppm. 13C
NMR (100 MHz, CDCl3): δ = 28.5, 48.9, 52.4, 54.6, 121.8, 124.5,
137.6, 150.6, 156.2, 164.3, 165.8 ppm. MS (ESI+): m/z (%) = 310.1
(100) [M + 1]+, 210.1 (56) [M + 1 – Boc]+. C15H23N3O4 (309.36):
calcd. C 58.24, H 7.49, N 13.58; found C 57.95, H 7.57, N 13.39.
Methyl 6-{[2-(tert-Butoxycarbonylamino)ethyl](propyl)amino}methyl-
nicotinate (18): To a solution of methyl ester 17 (1.60 g, 5.17 mmol,
1.0 equiv.) in CH3CN (40 mL) was added DIEA (5.31 mL,
31.02 mmol, 6.0 equiv.) and propyl bromide (2.35 mL, 25.9 mmol,
5.0 equiv.), and the mixture was stirred under reflux for 15 h. The
solvent was removed under reduced pressure, and the residue was
dissolved in CH2Cl2 (100 mL). The organic layer was washed with
H2O (2ϫ100 mL), dried with Na2SO4, and the solvents were evap-
orated. Column chromatography (CH2Cl2/MeOH, 98:2 Ǟ 95:5)
gave title compound 18 as a brown oil (1.36 g, 3.88 mmol, 75%).
1H NMR (400 MHz, CDCl3): δ = 0.85 (t, J = 7.4 Hz, 3 H, -CH2-
CH3), 1.42 (s, 9 H, -OtBu), 1.45–1.51 (m, 2 H, -CH2-CH3), 2.47 (t,
J = 7.4 Hz, 2 H, -CH2-CH2-CH3); 2.60 [t, J = 6.1 Hz, 2 H, -CH2-
N(propyl)-CH2-], 3.17 (td, J = 6.0, 5.7 Hz, 2 H, -CH2-NHBoc),
3.79, (s, 2 H, py-CH2-), 3.93 (s, 3 H, -CO2Me), 5.15 (br. s, 1 H,
-NH-), 7.50 (d, J = 8.2 Hz, 1 H, Harom.), 8.24 (dd, J = 8.1, 2.2 Hz,
1 H, Harom.), 9.11 (dd, J = 2.2, 0.8 Hz, 1 H, Harom.) ppm. 13C NMR
(100 MHz, CDCl3): δ = 11.8, 20.3, 28.5, 38.5, 52.3, 53.9, 56.7, 60.5,
122.4, 124.5, 137.5, 150.4, 156.1, 165.0, 165.9 ppm. MS (APCI+):
m/z (%) = 352.0 (100) [M + 1]+. C18H29N3O4 (351.44): calcd. C
61.52, H 8.32, N 11.96; found C 61.35, H 8.45, N 11.79.
Harom.), 8.49 (s, 1 H, Harom.), 9.07 (dd, J = 2.1, 0.6 Hz, 1 H, Harom.
)
ppm. 13C NMR (100 MHz, CDCl3): δ = 11.8, 20.5, 28.5, 45.7, 52.3,
52.7, 53.0, 53.5, 56.8, 60.9, 120.7, 121.7, 122.0, 122.1, 124.4, 136.7,
137.5, 149.2, 150.2, 155.8, 159.0, 166.0 ppm. MS (ESI+): m/z (%)
= 443.2 (100) [M + 1]+, 343.2 (42) [M – Boc + 1]+. C24H34N4O4
(442.55): calcd. C 65.14, H 7.74, N 12.66; found C 64.97, H 7.91,
N 12.47.
6-({2-[tert-Butoxycarbonyl(pyridine-2-ylmethyl)amino]ethyl(propyl)-
amino}methyl)nicotinic Acid (22): To a solution of methyl ester 21
(0.82 g, 1.85 mmol, 1.0 equiv.) in MeOH (15 mL) was added an
aqueous solution of NaOH (2 , 1.02 mL, 2.04 mmol, 1.1 equiv.),
and the mixture was heated to reflux for 1.5 h. The solvents were
removed, and the residue was dissolved in H2O (20 mL) and acidi-
fied with 2  HCl (pH 6). The aqueous phase was extracted with
CH2Cl2 (7ϫ20 mL). The combined organic layer was dried with
Na2SO4, and the solvents were evaporated to yield title compound
22 as a white solid (0.71 g, 1.66 mmol, 90%). 1H NMR (400 MHz,
CD3OD): δ = 0.94 (t, J = 7.3 Hz, 3 H, -CH2-CH3), 1.14 (s, 9 H,
OtBu), 1.28–1.39 (m, 2 H, -CH2-CH3), 1.61–1.85 (m, 2 H, -CH2-
CH2-CH3), 3.53 [t, J = 5.4 Hz, 2 H, -CH2-N(propyl)-CH2], 3.91 (t,
J = 5.5 Hz, 2 H, -CH2-NBoc-), 4.55 [s, 2 H, py-CH2-N(propyl)],
4.63 (s, 2 H, py-CH2-NBoc-), 7.31–7.42 (m, 2 H, Harom.), 7.53 (d,
J = 8.1 Hz, 1 H, Harom.), 7.85 (dd, J = 7.8, 7.8 Hz, 1 H, Harom.),
N-[(5-Methoxycarbonyl)pyridine-2-yl]methyl-N-propylethane-1,2-di-
aminium 2,2,2-trifluoroacetate (19): To a solution of methyl ester
Eur. J. Org. Chem. 2009, 4273–4283
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4281

R. A. Kramer, M. C. Bröhmer, N. V. Forkel, W. Bannwarth
FULL PAPER
8.31 (dd, J = 8.0, 2.1 Hz, 1 H, Harom.), 8.49–8.64 (m, 1 H, Harom.),
9.02 (s, 1 H, Harom.) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.3,
18.2, 28.3, 28.5, 44.7, 53.2, 53.4, 56.6, 56.91, 82.2, 123.8, 124.1,
26. After the washing steps solid support 40 was suspended in
CH2Cl2 (3 mL). After 10 min a solution of Grubbs 2nd generation
catalyst (6.8 mg, 0.008 mmol, 5 mol-%) in CH2Cl2 (2 mL) was
124.3, 133.2, 139.2, 139.4, 149.8, 151.6, 154.9, 157.1, 159.9, added. The solid support was agitated at room temperature for
171.0 ppm. MS (CI, NH3): m/z (%) = 429.2 (100) [M + 1]+.
C23H32N4O4 (428.52): calcd. C 64.46, H 7.53, N 13.07; found C
64.26, H 7.72, N 12.89.
24 h. After methanolysis of the solid support, methyl ester 41 was
obtained as a colorless liquid (7.4 mg, 59 µmol, 36%). The spectro-
scopic data were in accordance to those reported in the litera-
ture.[22]
Coupling of Tetradentate Linker 22 to the Solid Support and Subse-
quent Boc Deprotection to Yield Resin 26 Ready for the Attachment
of Carboxylic Acids: Hypogel400-NH2 (1.50 g, 1.04 mmol,
1.0 equiv.) was suspended in DMF (10 mL). After 10 min a solu-
tion of carboxylic acid 22 (604 mg, 1.41 mmol, 1.3 equiv.), TBTU
(453 mg, 1.41 mmol, 1.3 equiv.), and DIEA (1.11 mL, 6.48 mmol,
6.0 equiv.) in DMF (5 mL), which was preactivated for 5 min, was
added to the suspended resin. The solid support was agitated for
8 h. A negative Kaiser test showed complete coupling of carboxylic
acid 22. The solid support was filtered and washed alternately with
DMF/iPrOH (5ϫ5 mL), CH2Cl2 (5 mL), and Et2O (5 mL). The
resin was suspended in CH2Cl2 (15 mL) and after 10 min TFA
(15 mL) and iPr3SiH were added. The resin was agitated for 2 h and
was then washed again with DMF and iPrOH (5ϫ5 mL), CH2Cl2
(5 mL), and Et2O (5 mL). After drying under high vacuum modi-
fied resin 26 (1.91 g) was obtained.
D) Heck Reaction
(E)-Methyl 4-(3-Ethoxy-3-oxoprop-1-enyl)benzoate (42): p-Iodoben-
zoic acid (121.3 mg, 0.489 mmol, 3.0 equiv.) was coupled to solid
support 26. After the washing steps solid support 38 was suspended
in toluene. After 10 min Pd(OAc)2 (3.7 mg, 0.017 mmol, 10 mol-
%), PPh3 (12.8 mg, 0.0490 mmol, 30 mol-%), K2CO3 (112.8 mg,
0.816 mmol, 5.0 equiv.), NBu4Cl (45.4 mg, 0.163 mmol, 1.0 equiv.),
and ethyl acrylate (53.0 µL, 0.489 mmol, 3.0 equiv.) were added.
The solid support was heated to reflux for 4 d. After methanolysis
of the solid support, methyl ester 42 was obtained as a brown solid
(21 mg, 90 µmol, 55%). The spectroscopic data were in accordance
to those reported in the literature.[23]
E) Horner–Wadsworth–Emmons Reaction
(E)-Methyl 4-(3-Methoxy-3-oxoprop-1-enyl)benzoate (43): After
coupling of 4-carboxybenzaldehyde (73.4 mg, 0.489 mmol,
3.0 equiv.) to solid support 26 and after subsequent washing steps
solid support 36 was suspended in THF (1.5 mL) and cooled to
–78 °C. To a solution of diethoxyphosphorylacetic acid methyl es-
ter (89.5 µL, 0.490 mmol, 3.0 equiv.) in THF (3 mL) was added
dropwise at 0 °C nBuLi (1.5 , 350 µL, 0.490 mmol, 3.0 equiv.).
The resulting solution was cooled to –78 °C and added dropwise
to solid support 36. The resin was shaken at –78 °C for 3.5 h before
it was quenched by the addition of H2O/MeOH (1:1, 0.7 mL). After
the methanolysis, methyl ester 43 was obtained as a brown solid
(18.3 mg, 83 µmol, 51%). The spectroscopic data were in accord-
ance to those reported in the literature.[24]
Recycling of Linker 26: The amino acid Boc-Ala-OH was coupled
to solid support 26 by applying the general procedure. After meth-
anolysis by the general procedure Boc-Ala-OMe was obtained as a
white solid (19.9 mg, 0.098 mmol, 60%). The spectroscopic data
were in accordance to those reported in the literature.[17] After de-
complexation by the general procedure Boc-Phe-OH was coupled
to the solid support by applying the general procedure. Subsequent
methanolysis gave Boc-Phe-OMe as
a white solid (23.9 mg,
0.090 mmol, 55%). The spectroscopic data are in accordance to
those reported in literature.[18]
Reactions with Tetradentate Linker 26
A) Reductive Amination
F) Mitsunobu Reaction
Methyl 4-(Piperidin-1-ylmethyl)benzoate (37): 4-Carboxybenzalde-
hyde (73.4 mg, 0.489 mmol, 3.0 equiv.) was coupled to solid sup-
port 26 by the general procedure. After the washing steps solid
support 36 was suspended in DMF (5 mL) for 10 min before piperi-
dine (161 µL, 1.63 mmol, 10 equiv.) and NaBH(OAc)3 (345 mg,
1.63 mmol, 10 equiv.) were added. The solid support was agitated
for 12 h. After methanolysis of the solid support by the general
procedure, methyl ester 37 was obtained as an orange oil (19.4 mg,
83 µmol, 51%). The spectroscopic data were in accordance to those
reported in the literature.[19]
Methyl 4-(Allyloxy)benzoate (45): After coupling of 4-(tert-butyldi-
methylsilanyloxy)benzoic acid (176.0 mg, 0.489 mmol, 3.0 equiv.)
to solid support 26 and subsequent washing steps solid support 44
was suspended in DMF (4 mL). After 10 min a solution of Cs2CO3
(159.5 mg, 0.4896 mmol, 3.0 equiv.) in H2O (0.4 mL) was added.
The resin was agitated for 2 h, before it was washed alternately
with DMF/iPrOH (3ϫ5 mL) and CH2Cl2 (3ϫ5 mL). After the
deprotection, the resin was suspended under an atmosphere of ar-
gon in CH2Cl2 (2 mL) for 10 min before a solution of allyl alcohol
(50.1 µL, 0.734 mmol, 4.5 equiv.), DIAD (151.2 µL, 0.7834 mmol,
4.8 equiv.), and PPh3 (154.1 mg, 0.5875, 3.6 equiv.) in CH2Cl2
(1 mL) was added. The resin was agitated at room temperature for
20 h. After methanolysis of the solid support, methyl ester 45 was
obtained as a yellow oil (22.6 mg, 0.117 mmol, 72%). The spectro-
scopic data were in accordance to those reported in the litera-
ture.[25]
B) Suzuki–Miyaura Coupling
Methyl Biphenyl-4-carboxylate (39): p-Iodobenzoic acid (121.3 mg,
0.489 mmol, 3.0 equiv.) was coupled to solid support 26. After the
washing steps solid support 38 was suspended in DMF (5 mL).
After 10 min phenyl boronic acid (99.4 mg, 0.815 mmol, 5.0 equiv.),
K3PO4 (173 mg, 0.815 mmol, 5.0 equiv.), and Pd(PPh3)4 (18.5 mg,
0.016 mmol, 10 mol-%) were added. The solid support was agitated
at 90 °C for 12 h. After methanolysis of the solid support by the
general procedure, methyl ester 39 was obtained as a white solid
(16.6 mg, 78 µmol, 48%). The spectroscopic data were in accord-
ance to those reported in the literature.[20]
G) Grignard Reaction
Methyl 4-(1-Hydroxyallyl)benzoate (46): After coupling of 4-carb-
oxybenzaldehyde (73.4 mg, 0.489 mmol, 3.0 equiv.) to solid support
26 and after subsequent washing steps solid support 36 was sus-
pended under an atmosphere of argon in THF (5.0 mL). After
10 min vinylmagnesium chloride (1.5  in hexane, 532 µL,
0.816 mmol, 5.0 equiv.) was added dropwise at 0 °C. The resin was
agitated at room temperature for 15 h. After the methanolysis of
the solid support, methyl ester 46 was obtained as a brown oil
C) Ring-Closing Metathesis
Methyl Cyclopent-3-enecarboxylate (41): 2-Allyl-4-pentenoic acid
(68.5 mg, 0.489 mmol, 3.0 equiv.), which had been synthesized ac-
cording to a literature procedure,[21] was coupled to solid support
4282
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4273–4283

Tetradentate Linker for Amides To be Cleaved by Complexation
(17.4 mg, 0.0978 mmol, 60%). The spectroscopic data were in ac-
cordance to those reported in the literature.[26]
7.34 (m, 2 H, Harom.), 7.48–7.56 (m, 1 H, Harom.), 7.66 (s, 1 H,
-C=CH-), 7.80 (mc, 2 H, Harom.), 7.99 (mc, 3 H, Harom.) ppm. MS
(CI, NH3): m/z (%) = 294.1 (100) [M + 1]+. HPLC: tR = 11.31 min.
Reaction Sequences with Tetradentate Linker 26
A) Diazo Transfer and Click Reaction
(S)-Methyl 3-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propanoate
(47): After coupling of Fmoc-Phe-OH (189.3 mg, 0.489 mmol,
3.0 equiv.) to solid support 26 and after subsequent washing steps,
solid support 34 was suspended in DMF/piperidine (8:2, 2ϫ4 mL,
5 min) to yield the Fmoc-deprotected solid support. For the follow-
ing diazo transfer, a freshly prepared solution of triflic azide[14] in
pyridine (0.7 , 4.2 mL, 2.94 mmol, 18 equiv.), CuSO4·5H2O
(4.2 mg, 17 µmol, 10 mol-%), and MeOH (0.5 mL) were added to
the solid support. The solid support was agitated at room tempera-
ture for 20 h, before it was washed with DMF (3ϫ5 mL), DMF/
DIEA (99.5:0.5, 3ϫ5 mL, 2 min), diethyldithiocarbamate sodium
salt in DMF (0.05 , 3ϫ5 mL, 10 min), DMF (5ϫ3 mL, 5 min),
and CH2Cl2 (3ϫ5 mL, 3 min). The solid support was suspended in
DMF (3 mL). After 10 min phenylacetylene (37.6 µL, 0.342 mmol,
2.1 equiv.), -(+)-ascorbic acid (3.0 mg, 17 µmol, 10 mol-% equiv.),
and CuSO4·5H2O (0.9 mg. 3.6 µmol, 2 mol-%) were added. The so-
lid support was agitated at room temperature for 20 h. After meth-
anolysis of the solid support, methyl ester 47 was obtained as a
white solid (26.6 mg, 86 µmol, 53%). 1H NMR (400 MHz, CDCl3):
δ = 3.54 (m, 2 H, Ph-CH2-), 3.77 (s, 3 H, -CO2Me), 5.63 (t, J =
7.5 Hz, 1 H, MeO2C-CH-), 7.05–7.10 (m, 2 H, Harom.), 7.22–7.27
(m, 4 H, -CH=C-, Harom.), 7.32–7.36 (m, 1 H, Harom.), 7.42 (mc, 1
H, Harom.), 7.78–7.83 (m, 3 H, Harom.) ppm. MS (CI, NH3): m/z
(%) = 308.1 (100) [M + 1]+. HPLC: tR = 12.36 min.
[1] M. C. Bröhmer, W. Bannwarth, Eur. J. Org. Chem. 2008, 26,
4412–4415.
[2] N. Niklas, R. Alsfasser, Dalton Trans. 2006, 3188–3199.
[3] M. Kodma, E. Kimura, J. Chem. Soc., Dalton Trans. 1978,
1081–1085.
[4] K. Haas, W. Ponikwar, H. Nöth, W. Beck, Angew. Chem. Int.
Ed. 1998, 37, 1086–1089.
[5] M. O. O’Sullivan, D. M. Dalrymple, Tetrahedron Lett. 1995,
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2270.
[7] N. W. Alcock, A. C. Benniston, S. J. Grant, H. A. A. Omar, P.
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[8] A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryan-
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6, 287–292.
[10] P. Bigey, S. Frau, C. Loup, C. Claparols, J. Bernadou, B. Meun-
ier, Bull. Soc. Chim. Fr. 1996, 133, 679–689.
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[14] R.-B. Yan, E. Yang, Y. Wu, L.-H. Zhang, X.-S. Ye, Tetrahedron
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[15] M. A. Ilies, W. A. Seitz, B. H. Johnson, E. L. Ezell, A. L.
Miller, E. B. Thompson, A. T. Balaban, J. Med. Chem. 2006,
49, 3872–3887.
B) Sonogashira Reaction, TMS Deprotection, and Click Reaction
Methyl 4-(1-Benzyl-1H-1,2,3-triazol-4-yl)benzoate (48): After cou-
pling of p-iodobenzoic acid (121.3 mg, 0.489 mmol, 3.0 equiv.) to
solid support 26 and subsequent washing steps, solid support 38
was suspended under an atmosphere of argon in degassed DMF/
NEt3 (2:1, 4.5 mL). After 10 min ethinyltrimethylsilane (45.2 µL,
0.326 mmol, 2.0 equiv.), PdCl2(PPh3)2 (5.8 mg, 8.2 µmol, 5 mol-%),
PPh3 (8.6 mg, 32.6 mmol, 20 mol-%), and CuI (3.1 mg, 16 µmol
10 mol-%) were added to the solid support. The solid support was
heated to 80 °C for 24 h. After subsequent washing steps with
DMF, iPrOH, and CH2Cl2 the solid support was suspended in
THF (4 mL). After 10 min TBAF·3H2O (61.8 mg, 0.196 mmol,
1.2 equiv.) was added. The solid support was agitated at room tem-
perature for 24 h and again washed with DMF, iPrOH, and
CH2Cl2. The resulting solid support was suspended in DMF
(3 mL). After 10 min benzyl azide (43.5 mg, 0.326 mmol,
2.0 equiv.), -(+)-ascorbic acid (3.0 mg, 17 µmol, 10 mol-%), and
CuSO4·5H2O (0.9 mg, 3.6 µmol, 2 mol-%) were added. The solid
support was agitated at room temperature for 24 h. After subse-
quent washing steps with DMF (3ϫ3 mL), iPrOH (3ϫ3 mL), and
CH2Cl2 (3ϫ3 mL) and the following methanolysis of the solid sup-
port, methyl ester 48 was obtained as a yellow solid (19.6 mg,
66.8 µmol, 41%). 1H NMR (400 MHz, CDCl3): δ = 3.85 (s, 3 H,
-CO2Me), 5.51 (s, 2 H, Ph-CH2-), 7.22–7.27, (m, 1 H, Harom.), 7.29–
[16] S. W. Garrett, O. R. Davies, D. A. Milroy, P. J. Wood, C. W.
Pouton, M. D. Threadgill, Bioorg. Med. Chem. 2000, 8, 1779–
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Sánchez-Obregon, F. Walls, J. L. GarciaRuano, Tetrahedron:
Asymmetry 2000, 11, 3079–3090.
[18] A. Briot, M. Bujard, V. Gouverneur, C. Mioskowski, Eur. J.
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[21]
K. H. Bouhadir, J. Zhou, P. B. Shevlin, Synth. Commun. 2005,
35, 1003.
[22]
[23]
T. Ho, C. Chen, Helv. Chim. Acta 2005, 88, 2764–2770.
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Received: March 18, 2009
Published Online: July 21, 2009
Eur. J. Org. Chem. 2009, 4273–4283
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4283