Development of a new linker for the solid-phase synthesis of N-hydroxylated and N-methylated secondary amines

Tetrahedron 70 (2014) 1348e1356

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Development of a new linker for the solid-phase synthesis of N-hydroxylated and N-methylated secondary amines Denise Pauli, Stefan Bienz * € rich, Switzerland Institute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zu

a r t i c l e i n f o

a b s t r a c t

Article history: Received 1 October 2013 Received in revised form 28 November 2013 Accepted 4 December 2013 Available online 17 December 2013

Merrifield resin was modified by the introduction of an ortho-nitrophenylethanal group that served as a linker moiety to attach amines to the resin by reductive amination. Resin-bound tertiary amines were shown to be readily transferred into the respective liberated N-hydroxylated or N-methylated derivatives by either an oxidation/Cope elimination or a permethylation/Hofmann elimination protocol. With these two divergent liberation/derivatization options, the new resin offers new flexibility in the solid phase synthesis of N-modified secondary amines, for instance in spider toxin synthesis. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Solid-phase synthesis Linker N-Hydroxylation N-Methylation Secondary amine Spider toxin Cope elimination Hofmann elimination

1. Introduction Solid phase synthesis (SPS) has long since emancipated from being just the method of choice for the preparation of peptides and oligonucleotides. It also grew important for the synthesis of small molecules that became, e.g., efficiently accessible as libraries of similar structures (for a recent review article, see Ref. 1). Because the efforts for purification of synthetic intermediates are kept to a minimum, SPS has been established also for the preparation of products that would require laborious purification procedures along their synthesis. Such products are, for instance, polyamines and polyamine derivatives, such as spider toxins, for which SPS became standard procedure. So far, a number of SPS protocols have been developed to synthesize polyamine spider toxins or analogous structures. The more simple compounds that are not functionalized or substituted at the internal amino functions were efficiently prepared by stepwise construction of the polyamine backbones of the toxins through elongation of precursor moleculesdeither at one terminus2e15 or divergently at both terminid,16e20 followed by appropriate acylation, removal of protective groups, and cleaving off from the resins. A number of polyamine toxins, however, are more complex in their structures and contain N-methyl or N-hydroxyl groups. Examples * Corresponding author. Tel.: þ41 44 635 42 45; fax: þ41 44 635 68 12; e-mail addresses: [email protected], [email protected] (S. Bienz). 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.12.014

are, for instance, the toxins LF448A21 and AG432g22 from Larinioides folium and Agelenopsis aperta, respectively (Fig. 1). H N N H

O

N H

H N

N

NH2

Me

CONH2

LF448A

H N N H

O

OH N

H N

H N

NH2

O

AG432g

Fig. 1. Representative structures of N-hydroxylated and N-methylated spider toxins.

Since the structures of N-methylated and N-hydroxylated polyamine spider toxins are closely related to each other, access to common intermediates in their preparation would be desirable. Such intermediates could possibly be tertiary amines of the type A with an activating group (AG) positioned b to the N-atom. Compounds of this type would lead by permethylation or oxidation to structures of the type B or C and subsequently, upon regioselective Hofmann or Cope eliminations, to the desired products of the type D or E (Scheme 1). We thus planned to introduce an SPS system based on this concept,

D. Pauli, S. Bienz / Tetrahedron 70 (2014) 1348e1356

R2

ethy perm

R2 N

AG

R1

lation

N

AG

Me

R1

– AG

Me

B

oxid ation

A

R2

base

N O

R2 R1

– AG

HO

C

H H O

R1

O

R2 N

O

R1

O activation by aryl

H H

Br O

N

E

activation by carboxyl

1

R1

D R2

AG

N

R1 N

R

O

R2

1349

allowed proper control of the reaction conditions and appropriate analysis of the products. As the model compounds, the three phenethyl bromides 4aec were selected. While compound 4a represents the direct model for Seo’s resin 2, the benzyloxy group mimicking the attachment to the Merrifield resin, compound 4c stands for the newly proposed linker in 3. Finally, homobenzyl bromide (4b) was chosen as a third electronically unbiased substrate, carrying neither a donating (alkoxy) nor an accepting (nitro) group. The three bromides 4aec43 were treated with bis-phthalprotected spermidine 544 in the presence of NaI and diisopropylethylamine (DIEA) to deliver the corresponding tertiary amines 6aec in 46, 36, and 8% yields, respectively (Scheme 2). While the reactions of 4a and 4b were rather slow, not coming to completion in 120 h at 50 , the substitution reaction with 4c was problematic with regards to a side reaction: it was accompanied by the elimination of HBr, which delivered the respective styrene product in a yield of as high as 55%.

R NPhth

2 R=H 3 R = NO2

HN

Br R1

N

5

Scheme 1.

which finally would not only open the efficient combinatorial access to N-modified polyamine spider toxins but also to N-hydroxylated secondary amines, tertiary amines, and their respective analogs in general. This is of relevance because tertiary amines are important structural units of biological active compoundsdno less than a quarter of the registered drugs were estimated to contain tertiary aminesd,23 and N-hydroxylated amines are interesting as synthetic intermediates (for some more recent examples see Refs. 24e29) or due to their biological activities, being unique or, in some cases, similar to the activities of their parent amines.30e35 In fact, Morphy et al. had already introduced with their REM resin (1, Scheme 1) a solid-phase system that would, in principle, allow to access both types of products D and E by the reactions proposed above.23,36e40 While their permethylation/Hofmann elimination protocol indeed delivered the desired products efficiently, the oxidation/Cope elimination process, however, proved less suitable.41 Due to the strong activation of the H atoms in aposition to the carboxyl group, Cope elimination of the respective compounds of the type C proceeded prematurely already during the washing of the resins. To circumvent this problem, Seo et al. introduced the phenethyl resin 2.42 This resin was finally used successfully in the preparation of some spider toxin precursors by us.20 Preliminary experiments revealed, however that resin 2 is not optimally suited for our purposes: (1) our attempts to prepare Nmethylated amines by permethylation and Hofmann elimination delivered only marginal amounts of the desired products and (2) closer analysis of the side products formed upon oxidation/Cope elimination indicated that the regioselectivity of the cleavage reaction is not complete.43 Apparently, the benzylic H atoms are not appropriately activated to allow facile Hofmann elimination and to secure full Cope elimination towards the desired site of the molecule. As an alternative to resin 2 we thus propose resin 3 with the ortho-nitrophenethyl moiety as the linker. The additional NO2 group at the aromatic system should enhance the acidity of the benzylic H-atoms and facilitate the desired elimination reactions.

NPhth

NPhth

NaI, DIEA, DMF

R2

R1

4a = BnO =H 4b R1 = H R2 = H 1 2 4c R = BnO R = NO 2 R1

NPhth

R2

6a = BnO R 2 = H 6b R1 = H R2 = H 6c R1 = BnO R 2 = NO 2

R2

R1

(46%) (36%) (8%)

Scheme 2.

The problem of HBr-elimination was overcome by using aldehyde 10 instead of bromide 4c as the precursor to attach the amine. Aldehyde 10 was readily prepared in a three step procedure from toluene derivative 7 (Scheme 3). Reaction of 7 with BnBr in presence of base afforded in the initial step O-benzyl-protected derivative 8 (93%). This compound delivered enamine 9 upon its treatment with N,N-dimethyl formamide dimethyl acetal (DMFDMA) in presence of pyrrolidine45 and, finally, aldehyde 10 (76%) after acidic hydrolysis. Loading of the spermidine derivatives 5 and 11 onto the resin model was effected by reductive amination. Treatment of aldehyde 10 with the secondary amines and NaBH(OAc)3 in presence of AcOH46 delivered 6c and its bis-Bocprotected analog 12 in 86% and 62% yield. N(H)PG Me RO

N

NO 2

BnO

7 R=H 8 R = Bn (93%) DMF-DMA pyrrolidine DMF

NO 2

BnO

NO 2

6c N(H)PG = NPhth (86%) 12 N(H)PG = NHBoc (62%)

BnBr, K 2CO 3 DMF

N

N(H)PG

NaBH(OAc) 3 AcOH ClCH 2CH 2Cl

N(H)PG HN

N(H)PG

5 N(H)PG = NPhth 11 N(H)PG = NHBoc

HCl (10% aq.) CH 2Cl 2

9

CHO BnO

NO 2

10 (76%) Scheme 3.

2. Results and discussion 2.1. Study with model compounds To initialize our study, the potential of resin 3 was investigated with reactions performed in solution with model compounds. This

To test the influence of the linker moieties on the regioselectivities of the Cope eliminations, the three tertiary amines 6aec with the Phth-chromophores were used. They were oxidized to the respective N-oxides 13aec by treatment with m-CPBA (Scheme 4). After removal of the excess of the oxidizing reagent and of the

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D. Pauli, S. Bienz / Tetrahedron 70 (2014) 1348e1356

NPhth O

NPhth N

+

NPhth R1

R1

N

HO

NPhth

14

R2

R2

13a–13c

NPhth N R1

R2

OH

Ratios: a: R1 = BnO b: R1 = H c: R1 = BnO

+

15a–15c +

14: 15a: 16a R2 = H 14: 15b: 16b R2 = H 2 R = NO 2 14: 15c: 16c

NPhth

NPhth

OH

80: 15: 5 90: 8: 2 97: 2: 1

N

NPhth

R 2 16a–16c

R1

Scheme 4.

acidic byproduct, the N-oxides were heated in toluene to 90 for 2 h, and the product distributions of 14, 15aec, and 16aec were then analyzed by HPLC. The relative amounts of the three products of the type 14, 15, and 16 for each starting material were assessed from the related peak areas in the chromatograms, detected at 300 nm with a UV(DAD) detector, taking the number of chromophores and their extinction coefficients at 300 nm into account. From the results summarized in Scheme 4 it is readily recognized that in fact the new linker moiety contained in 13c is superior to the alternative arylethyl groups of 13a and 13b in promoting regioselective Cope elimination. The reaction of 13c provided as much as 97% of the desired N-hydroxylated triamine derivative 14 and only 2%, respectively, 1% of the undesired products of the type 15 and 16, while the respective ratios for the analogs 13a and 13b were 80:15:5% and 90:8:2%. Thus, increased yields in the extent of approximately 20% can be expected by using a resin of the type 3 instead of Seo’s resin 2 for the synthesis of N-hydroxylated amines on solid support. Since smaller amounts of side products are formed, the desired products arise also in higher purity, which reduces the efforts needed in the final purification step. To study the potential of the new linker for the synthesis of Nmethylated tertiary amines by methylation/Hofmann elimination, initially model compound 6c was studied. It was treated with an excess of MeI to afford ammonium salt 17 (Scheme 5), which then was exposed to different bases in the attempt to effect the desired elimination reaction to tertiary amine 18.

rate. All starting material was consumed after 15 min, however, no product was isolated since the phthalimides of 18 got partially hydrolyzed during the reaction and the aqueous extractive work-up that was performed to remove the potassium salts formed during the reaction. No such problem occurred with ammonium compound 19, the bis-N-Boc analog of 17, which was obtained by permethylation of tertiary amine 12. Treatment of 19 with tBuOK in CH2Cl2 for 15 min delivered the desired amine 20 in excellent 91% yield. 2.2. Synthesis and characterization of the new resin Since it turned out that an aldehyde is advantageously used as the functional group to attach an amine to a 2-nitrophenethyl moiety, resin 24 rather than resin 3 was proposed as the new starting material for the SPS of N-hydroxylated and N-methylated amines (Scheme 6). Taking advantage of the benefits of SPS already in an early stage, the linker moiety of 24 was synthesized analogously to compound 10 directly on the resin. Hence, commercial toluene derivative 7 was loaded in a first step onto Merrifield resin 21 (ca. 0.80 mmol g1). Treatment of the thus obtained toluene derivative 22 with DMF-DMA in presence of pyrrolidine afforded enamine resin 23 and, finally, after aqueous acidic hydrolysis, the desired aldehyde resin 24.

Cl

Me

BnO

N(H)PG N

N(H)PG

+

NaH HO

NO 2

21 base

NO 2

O

NO 2

DMF

7

22

N(H)PG Me

17 N(H)PG = NPhth (92%) 19 N(H)PG = NHBoc (86%)

Me

Me

N

DMF-DMA pyrrolidine DMF

N(H)PG

18 N(H)PG = NPhth (<80%) 20 N(H)PG = NHBoc (91%) Scheme 5.

HCl (10% aq.) O

NO 2

24

It turned out that no reaction was observed within a reasonable period of time when rather weak amine bases were used, such as DIEA (diisopropylethylamine) or DABCO (1,4-diazabicylo[2.2.2]octane) with estimated pKa values for the conjugate acids in DMSO of 8.5 and 8.9, respectively. With the stronger amidine base DBU (1,6diazabicyclo[5.4.0]undec-7-ene, pKa 13.9), however, Hofmann elimination was successfully effected, and the desired product 18 was isolated in 80% yield. The elimination reaction was rather slow, though, and purification of the product was laborious due to the DBU, which was difficult to remove from the desired product. Using the even stronger oxide base tBuOK (pKa 31) increased the reaction

N

CHO O CH 2Cl 2

NO 2

23

Scheme 6.

The functional loading capacity of resin 24, which represents the maximal amount of material that can effectively be obtained by SPS on the solid support, was determined chemically. To this purpose, the two secondary amines 5 and 11 already used in the model reactions were loaded onto 24 to form resins 25 and 26 (Scheme 7). Resin 25 was then oxidized and heated analogously to 6c to deliver N-hydroxylated product 14, while resin 26 was permethylated and

D. Pauli, S. Bienz / Tetrahedron 70 (2014) 1348e1356

1351

N(H)PG CHO O

N

1. 5 or 11 ClCH 2CH 2Cl

NO 2

24 (1.0 g)

O 2. NaBH(OAc) 3 AcOH

N(H)PG

oxididation/ Cope elimination or

N(H)PG

NO 2

X

25 N(H)PG = NPhth 26 N(H)PG = NHBoc

methylation/ Hofmann elimination

N

N(H)PG

14 N(H)PG = NPhth X = HO (0.284 mmol) 20 N(H)PG = NHBoc X = Me (0.284 mmol)

Scheme 7.

treated with tBuOK analogously to 12 to afford tertiary amine 20. The two products 14 and 20 were obtained in the same amounts (0.284 mmol per g resin 24) revealing the functional loading capacity of the resin. The superiority of the new resin 24 over Seo’s resin 2 for the preparation of N-hydroxylated polyamines can be well demonstrated with the 1H NMR spectra obtained from the crude products of 14, prepared once using resin 24 and once using resin 2 (spectra a and b, Fig. 2). While spectrum (a) accounts for a virtually pure sample of 14, the signals in the region of the olefinic protons (d¼5e6 ppm) and the signals at approximately d¼4.3 and 3.5 ppm of spectrum (b) indicate the formation of considerable amounts of olefinic side products, derived from Cope elimination towards the undesired sites of the molecule.

Fig. 2. Comparison of the 1H NMR spectra of crude N-hydroxylated triamine derivative 14 obtained by (a) using the new resin 24 and (b) using the related resin 2 of Seo et al. without the additional ortho nitro group.

2.3. Construction of a triamine derivative on the new resin For the divergent SPS of polyamine derivatives ‘from the center’, triamine resins of the type 30, with orthogonally protected terminal amino groups, are required as intermediates (Scheme 8). Such compounds could be obtained by direct coupling of the respective unsymmetrically bis-protected secondary amines with resin 24 or by stepwise construction of the triamine portion on the resin. The former would require ‘in-solution’ chemistry that might be laborious, the latter would increase the number of steps performed on the resin that might reduce the overall yield of the SPS. Depending on the exact problem, the appropriate compromise has to be chosen individually. To evaluate the loss of yield that has to be taken into account by choosing a stepwise construction of the triamine portion on the resin, N-hydroxyl and N-methyl triamine derivatives 31 and 32 were prepared this way (Scheme 8). Treatment of resin 24 with primary amine 2747 under the usual conditions of reductive amination delivered resin 28, and condensation of this compound with aldehyde 2948 followed by reduction with NaBH(OAc)3 afforded the desired resin 30. Oxidation/Cope elimination or methylation/Hofmann elimination, finally, released the N-hydroxylated and Nmethylated triamine derivatives 31 and 32 in comparable yields of 69% and 75%. Thus, approximately 30% of material was lost due to the stepwise construction of resin 30. We have indication that two competitive reactions, occurring during the initial reductive amination of 24 with the primary amine 27, are responsible for this loss of material. (1) We think that crosslinking through intramolecular reductive amination of the secondary amine of resin 28 with a neighboring aldehyde group takes placeda reaction that cannot occur when a secondary amine is loaded onto the resin. This assumption is supported by the fact that the drop in yield is considerably more pronounced when a resin with a higher loading capacity was used.49 (2) We believe that the reductive amination of 24 with primary amines is not as

NHNs

1. CHO O

NO 2

24

NH

NHNs

27

NH

ClCH 2CH 2Cl 2. NaBH(OAc) 3 AcOH

O

NO 2

28 1.

O

NHBoc

29

ClCH 2CH 2Cl 2. NaBH(OAc) 3 AcOH NHNs N

X

N

31 32

X = HO X = Me

NHNs

oxid./Cope elim. or

NHBoc

meth./Hofmann elim.

O

NO 2

30

(69%) (75%)

Scheme 8.

NHBoc

1352

D. Pauli, S. Bienz / Tetrahedron 70 (2014) 1348e1356

efficient as with secondary amines, and that competitive reduction of the aldehyde group in 24 occurs. According to Abdel-Magit et al., who have investigated reductive aminations with NaBH(OAc)3 as the reducing agent in more detail,46 such competitive aldehyde reduction can become significant when imine formation is slow. We have experienced that the reaction sequence of above, performed with a shorter and, thus, sterically more hindered propandiamine derivative, delivered substantially less of the desired product. 3. Conclusion We have shown that (1) the newly designed resin 24 can readily be prepared by on-resin synthesis starting from commercial products and that (2) this resin can be used for the efficient and convergent preparation of either N-hydroxylated or N-methylated amine derivatives. Both secondary and primary amines can be attached to the resins by reductive amination, but the reaction is more efficient for secondary amines. For the preparation of unsymmetrically, orthogonally protected triamine intermediates, the choice between optimized yields and ease of procedures has to be made. 4. Experimental 4.1. General Starting materials were purchased from commercial suppliers and used without further purification. For NaBH(OAc)3, it was necessary to shrunk the clots before usage. All reactions in solution were carried out under an argon atmosphere in dried apparatus with dry solvents (puriss. grade over molecular sieve sealed with a crown cap purchased from SigmaeAldrich). Organic extracts were dried with MgSO4 and the solvents removed by evaporation in vacuo at 40  C. Column chromatography was performed with silica gel (pore size 60  A, particle size 40e63 mm, 0.1% Ca) from Fluka and freshly distilled solvents of technical grade. Solid-phase reactions were carried out with an Advanced ChemTech PLS 6 synthesizer. The resin used was Merrifield Peptide Resin, 200e400 mesh with 1% DVB, 0.8 mmol g1 loading (Advanced ChemTech). UV spectra: Cary Series spectrophotometer (Agilent technologies); lmax (ε) in nm. IR spectra were recorded with solids or films on a Jasco FT/IR-4100 using the Golden Gate (ATR) method. Compounds 6a and 6b were recorded as films on a Perkin Elmer IR ‘Spectrum One’ spectrophotometer. The wavenumbers (1/l) are given in cm1 (for resins, only the diagnostic signals are reported). Melting points were measured with a Mettler FP 5. NMR spectra were recorded on Bruker AV-300, AV-400, AV-500 or AV-600 MHz instruments. Chemical shifts (d) are given in parts per million relative to peaks of residual solvents CHCl3 (for 1H: d 7.26 ppm; for 13C: 77.16 ppm). The coupling constants J are reported in Hertz. Multiplicities of 13C signals were derived from DEPT-135 and DEPT-90 measurements. EI-MS were performed on a Thermo DFS (ThermoFisher Scientific) double-focusing magnetic sector mass spectrometer (geometry BE). Mass spectra were measured in electron impact (EI) mode at 70 eV, with solid probe inlet, source temperature of 200  C, acceleration voltage of 5 kV, and resolution of 2500. The instrument was scanned between m/z 30 and 900 at scan rate of 2 s/decade in the magnetic scan mode. Perfluorokerosene (Fluorochem) served for calibration. ESI-MS measurements were performed on a Bruker ESQUIRE-LC quadrupole ion trap instrument (Bruker Daltonik GmbH), equipped with a combined HewlettePackard Atmospheric Pressure Ion (API) source. The solns (about 0.1e1 mmol ml1) were continuously introduced through the electrospray interface with a syringe infusion pump (Cole-Parmer 74900-05) at a flow rate of 5 ml min1. The MS acquisitions were performed at normal resolution (>1000 full width at

half maximum), in the mass range from m/z 100 to 2000. To get representative mass spectra, eight scans were averaged. HR-ESI-MS measurements were performed on a Bruker maXis quadrupole time-of-flight instrument (Bruker Daltonik GmbH), equipped with a combined HewlettePackard Atmospheric Pressure Ion (API) source. The solns (about 10e100 nmol ml1) were continuously introduced through the electrospray interface with a syringe infusion pump (Cole-Parmer 74900-05) at a flow rate of 3 ml min1. MS acquisitions were performed in the mass range from m/z 50 to 2000 at 20,000 resolution (full width at half maximum) and 1.0 Hz spectra rate. Masses were calibrated below 2 ppm accuracy between m/z 158 and 1450 (calibration with 2 mM soln NH4HCO2Na) prior analysis. Signals of intensities 5 rel% as well as molecular ions and characteristic fragments are reported with their m/z values (in mass units, u) and with their intensities in rel% in brackets. 4.2. Synthesis of the model compounds 4.2.1. N,N0 -{4-[2-(4-Benzyloxyphenyl)ethyl]-4-azaoctane-1,8-diyl}bis [phthalimide] (6a). To a soln of N,N0 -(4-azaoctane-1,8-diyl}bis [phthalimide]44 (5, 5.52 g, 13.61 mmol), NaI (1.16 g, 7.73 mmol), and diisopropylethylamine (DIEA, 3.2 ml, 18.37 mmol) in dry DMF (70 ml) at 50  C, 2-(4-benzyloxyphenyl)ethyl bromide43 (4a, 2.00 g, 6.87 mmol) in dry DMF (10 ml) was added dropwise. The mixture was stirred for 5 d at 50  C, and the DMF was removed in vacuo. H2O was added, and it was extracted with CH2Cl2. Column chromatography (CH2Cl2/MeOH/NEt3 100:1:1) gave 6a (1.96 g, 3.18 mmol, 46%) as a yellow oil. IR: 3464w, 3221w, 3060m, 3026m, 2942s, 2863m, 2806m, 1770s, 1723s, 1614m, 1495m, 1466s, 1437s, 1397s, 1367s, 1335s, 1267w, 1187m, 1088m, 1037s, 892m, 793m, 720s. 1H NMR (600 MHz): 7.84e7.81 (m, 4H); 7.71e7.67 (m, 4H); 7.44e7.29 (m, 5H); 7.09e7.06 (m, 2H); 6.88e6.86 (m, 2H); 5.02 (s, 2H); 3.72e3.66 (m, 4H); 2.65e2.59 (m, 4H); 2.54 (t, J¼7.0, 2H); 2.49 (t, J¼7.3, 2H); 1.82 (quint., J¼7.2, 2H); 1.70e1.65 (m, 2H); 1.48e1.43 (m, 2H). 13C NMR (150 MHz): 168.6 (s, 2C); 168.5 (s, 2C); 157.2 (s); 137.4 (s); 134.0 (d, 4C); 132.4 (s, 2C); 132.3 (s, 2C); 130.0 (s); 129.8 (d, 2C); 128.7 (d, 2C); 128.0 (d); 127.6 (d, 2C); 123.30 (d, 2C); 123.29 (d, 2C); 114.9 (d, 2C); 70.2 (t); 56.1 (t); 53.5 (t); 51.8 (t); 38.0 (t); 36.6 (t); 32.8 (t); 26.6 (t); 26.5 (t); 24.6 (t). ESI-MS: 616 (100, [MþH]þ). 4.2.2. N,N0 -[4-(2-Phenylethyl)-4-azaoctane-1,8-diyl]bis[phthalimide] (6b). Analogous to Section 4.2.1, bis[phthalimide] 544 (2.24 g, 5.50 mmol) was reacted with commercially available 2-phenylethyl bromide (4b, 1.13 g, 6.11 mmol) in presence of NaI (1.15 g, 7.67 mmol) and DIEA (2.8 ml, 16.1 mmol) in dry DMF at 50  C for 65 h. Column chromatography (CH2Cl2/MeOH/NEt3 100:1:1) gave 6b (1.11 g, 2.18 mmol, 36%) as a yellow oil. IR: 3464w (br), 3061m, 3031m, 2940s, 2864m, 2806m, 1770s, 1721s, 1611s, 1583s, 1510s, 1466s, 1454s, 1436s, 1395s, 1334s, 1299m, 1239s, 1175m, 1115m, 1088m, 1038s, 892w, 863w, 823m, 793w, 720s, 697m. 1H NMR (400 MHz): 7.83e7.79 (m, 4H); 7.71e7.67 (m, 4H); 7.25e7.11 (m, 5H); 3.72e3.65 (m, 4H); 2.73e2.65 (m, 4H); 2.53 (m, 4H); 1.85 (quint., J¼7.2, 2H); 1.71e1.64 (m, 2H); 1.52e1.44 (m, 2H). 13C NMR (100 MHz): 168.51 (s, 2C); 168.45 (s, 2C); 140.5 (s); 133.9 (d, 4C); 132.31 (s, 2C); 132.29 (s, 2C); 128.8 (d, 2C); 128.4 (d, 2C); 126.0 (d); 123.27 (d, 2C); 123.26 (d, 2C); 55.7 (t); 53.3 (t); 51.7 (t); 37.9 (t); 36.5 (t); 33.4 (t); 26.6 (t); 26.3 (t); 24.4 (t). ESI-MS: 510 (100, [MþH]þ). 4.2.3. N,N0 -{4-[2-(4-Benzyloxy-2-nitrophenyl)ethyl]-4-azaoctane1,8-diyl}bis[phthalimide] (6c)dby substitution of 2-(4-benzyloxy-2nitrophenyl)ethyl bromide (4c). Analogous to Section 4.2.1, bis [phthalimide] 544 (2.24 g, 5.50 mmol) was reacted with 2-(4benzyloxy-2-nitrophenyl)ethyl bromide43 (4c, 0.81 g, 2.40 mmol) in presence of NaI (0.45 g, 3.0 mmol) and DIEA (2 ml) in dry DMF at 50  C. Column chromatography (CH2Cl2/MeOH/NEt3 100:1:1) gave 6c (0.12 g, 0.18 mmol, 8%) as a yellow oil.dBy reductive amination of

D. Pauli, S. Bienz / Tetrahedron 70 (2014) 1348e1356

aldehyde 10 (preparation of 10 see below). To a soln of aldehyde 10 (449 mg, 1.66 mmol) in dry 1,2-dichloroethane (DCE, 10 ml) at 23  C, bis[phthalimide] 544 (0.74 g, 1.8 mmol) and AcOH (100%, 0.12 ml, 2.1 mmol) were added. After stirring for 15 min, NaBH(OAc)3 (0.70 g, 3.3 mmol) was added, and the resulting suspension was stirred for an additional 3 h. The excess of reagent was quenched by the addition of a satd aq soln of NaHCO3. The organic layer was washed with a satd aq soln of NaHCO3 and with brine. Column chromatography (CH2Cl2/MeOH with a gradient from 100:1 to 100:3) gave 6c (0.94 g, 1.43 mmol, 86%) as a yellow oil. IR: 2941w, 2812w, 1770w, 1708s, 1617w, 1527m, 1464w, 1438w, 1395m, 1364w, 1247w, 1188w, 1034w, 719m, 533w. 1H NMR (300 MHz): 7.85e7.79 (m, 4H); 7.72e7.66 (m, 4H); 7.48 (d, J¼2.7, 1H); 7.45e7.34 (m, 5H); 7.26 (d, J¼8.5, 1H); 7.13 (dd, J¼8.5, 2.7, 1H); 5.09 (s, 2H); 3.79 (q-like m, J¼ca. 7.5, 4H); 2.94e2.89 (m, 2H); 2.70e2.65 (m, 2H); 2.58e2.48 (m, 4H); 1.81 (quint., J¼7.2, 2H); 1.69 (quint., J¼7.4, 2H); 1.50e1.40 (m, 2H). 13 C NMR (75 MHz): 168.55 (s, 2C); 168.51 (s, 2C); 157.3 (s); 149.8 (s); 136.1 (s); 133.9 (d, 4C); 133.7 (d); 132.4 (s, 2C); 123.3 (s, 2C); 128.8 (d, 2C); 128.4 (d); 128.1 (s); 127.7 (d, 2C); 123.3 (d, 4C); 120.6 (d); 110.4 (d); 70.6 (t); 54.6 (t); 53.3 (t); 51.6 (t); 38.0 (t); 36.5 (t); 30.1 (t); 26.6 (t, 2C); 24.7 (t). ESI-MS: 661 (100, [MþH]þ). 4.2.4. 4-Benzyloxy-2-nitrotoluene (8, prepared analogous to Ref. 50). 4-Methyl-3-nitrophenol (7, 13.80 g, 90.1 mmol) was dissolved in dry DMF (75 ml), and K2CO3 (17.42 g, 126.0 mmol) and BnBr (10.8 ml, 90.3 mmol) were added at 23  C. The mixture was heated to 100  C for 90 min, allowed to cool to 40  C, and freed of the solvent by evaporation in vacuo. An aq soln of NaOH (2 M) was added, it was extracted with EtOAc, and the extracts were washed with brine. Recrystallization from MeOH delivered 8 (20.41 g, 83.9 mmol, 93%) as pale yellow plates. Mp 50.0e50.5  C (MeOH). IR: 3033w, 2932w, 1622w, 1571w, 1523s, 1498m, 1453m, 1407w, 1382w, 1345m, 1305m, 1280m, 1239s, 1200w, 1150w, 1065w, 1018m, 908w, 846w, 811m, 736m, 696m, 525w. 1H NMR (300 MHz): 7.59 (d, J¼2.7, 1H); 7.44e7.33 (m, 5H); 7.22 (d, J¼8.4, 1H); 7.12 (dd, J¼8.4, 2.7, 1H); 5.09 (s, 2H); 2.52 (s, 3H). 13C NMR (75 MHz): 157.3 (s); 149.5 (s); 136.1 (s); 133.6 (d); 128.9 (d, 2C); 128.5 (d); 127.7 (d, 2C); 126.0 (s); 120.8 (d); 110.4 (d); 70.7 (t); 19.9  (q). EI-MS: 243 (3, Mþ ), 213 (2, [MNO]þ), 91 (100, [C7H7]þ), 77 (2, þ [C6H5] ), 65 (8). Anal. Calcd for C14H13NO3: C 69.12, H 5.39, N 5.76. Found: C 69.16, H 5.35, N 5.58. 4.2.5. 2-(4-Benzyloxy-2-nitrophenyl)ethanal (10, prepared analogous to Ref. 45). To a soln of 8 (6.69 g, 27.5 mmol) in dry DMF (40 ml) at 23  C, N,N-dimethyl formamide dimethyl acetal (DMFDMA, 5.5 ml, 41.3 mmol) and pyrrolidine (3.4 ml, 41.1 mmol) were added. The mixture was heated to 120  C for 3 h, allowed to cool to 40  C, and freed of the volatile components by evaporation in vacuo. The dark purple solid residue of the intermediary enamine 9 was dissolved in CH2Cl2 (50 ml), and an aq soln of HCl (10%, 20 ml) was added. The mixture was heated to 40  C for 2.5 h, then allowed to cool to 23  C. The two phases were separated, the aq phase was extracted with CH2Cl2, and the combined organic phases were washed with brine. Recrystallization from Et2O delivered 10 (5.67 g, 20.9 mmol, 76%) as an orange-brown solid. Mp 58.9e60.7  C (Et2O). IR: 1723m, 1621w, 1570w, 1524s, 1498m, 1454w, 1382m, 1345m, 1243s, 1018m, 929w, 844w, 810m, 738m, 697m. 1H NMR (300 MHz): 9.82 (t, J¼0.8, 1H); 7.76e7.75 (m, 1H); 7.45e7.34 (m, 5H); 7.22e7.21 (m, 2H); 5.13 (s, 2H); 4.03 (d, J¼0.8, 2H). 13C NMR (75 MHz): 197.4 (d); 158.7 (s); 149.4 (s); 135.7 (s); 134.4 (d); 128.9 (d, 2C); 128.6 (d); 127.7 (d, 2C); 121.2 (d); 120.6 (s); 111.2 (d); 70.8  (t); 48.0 (t). EI-MS: 271 (1, Mþ ), 91 (100, [C7H7]þ), 77 (2, [C6H5]þ), 65 (10). 4.2.6. Di-tert-butyl-N,N0 -{4-[2-(4-benzyloxy-2-nitrophenyl)ethyl]-4azaoctane-1,8-diyl}bis[carbamate] (12). Analogous to Section 4.2.3,

1353

aldehyde 10 (457 mg, 1.68 mmol) was condensed with bis[carbamate] 1144,51 (682 mg, 1.97 mmol) in presence of AcOH (100%, 0.12 ml, 2.1 mmol) and reduced with NaBH(OAc)3 (721 mg, 3.40 mmol) in dry DCE at 23  C for 4 h. Column chromatography (CH2Cl2/MeOH with a gradient from 100:2 to 100:10) gave 12 (622 mg, 1.04 mmol, 62%) as a yellow oil. IR: 3351w (br), 2974w, 2933w, 2867w, 2814w, 1694s, 1621w, 1526s, 1454m, 1390m, 1363m, 1248s, 1167s, 1077w, 1020m, 910w, 852w, 813w, 736m, 698m. 1H NMR (300 MHz): 7.51 (d, J¼2.6, 1H); 7.44e7.32 (m, 5H); 7.25 (d, J¼8.7, 1H); 7.13 (dd, J¼8.7, 2.6, 1H); 5.25 (br s, 1H); 5.09 (s, 2H); 4.80 (br s, 1H); 3.18e3.08 (br m, 4H); 2.98e2.93 (br m, 2H); 2.71e2.66 (br m, 2H); 2.55e2.49 (br m, 4H); 1.65e1.60 (br m, 2H); 1.48 (br s, 4H) overlaying with 1.43 (s, 18H). 13C NMR (75 MHz): 157.5 (s); 156.2 (s, 2C); 149.8 (s); 136.0 (s); 133.6 (d); 128.8 (d, 2C); 128.5 (d); 127.6 (d, 2C); 120.7 (d); 110.5 (d); 79.0 (br s, 2C); 70.7 (t); 54.6 (t); 53.4 (t); 52.3 (t); 40.5 (br t); 39.7 (br t); 29.9 (t); 28.58 (q, 3C); 28.57 (q, 3C); 28.0 (t); 27.0 (br t); 24.4 (br t). The signal of one quaternary C was not found in the spectrum; we assume that it is hidden underneath another signal. ESI-MS: 601 (100, [MþH]þ).

4.3. Oxidation/Cope eliminations with the model compounds 6aec to determine the regioselectivities in dependence of the activating arylethyl group 4.3.1. N,N0 -(4-Hydroxy-4-azaoctane-1,8-diyl)bis[phthalimide] (14) and alkene derivatives of the types 15 and 16: general procedure. A triamine derivative of the type 6 (0.10 mmol) was dissolved in dry CH2Cl2 (2 ml), and the soln was cooled to 0  C. m-CPBA (0.10 mmol), dissolved in dry CH2Cl2 (2 ml), was added dropwise. It was stirred for 3 h and filtered through a short column of basic Al2O3 (CH2Cl2, then CH2Cl2/MeOH 3:1) to remove the acidic byproducts. The solvents were removed in vacuo, toluene (3 ml) was added, and the mixture was heated to 90  C for 2 h. After removal of the toluene by evaporation in vacuo, the residue was analyzed by HPLC-UV(DAD)MS as described below. Compound 14 is fully characterized under Section 4.6.2. 4.3.2. Determination of the regioselectivities. Two transformations with each model compound 6aec were performed according to Section 4.3.1, and the crude products were analyzed by HPLCUV(DAD)-ESI-MS, using a Kromasil K100 10C18 column (2504.6 mm) under reversed-phase conditions with H2O/MeCN/ TFA 60:40:0.1 (isocratic) as the eluent at a flow rate of 1 ml min1. The analytes were identified by their [MþH]þ ion responses in ESIMS: 14: tR¼6.4e7.1 min, m/z 422; 15a: tR¼35.7e38.5 min, m/z 445; 15b: tR¼9.1e9.5 min, m/z 339; 15c: tR¼45.5e46.8 min, m/z 490; 16a: tR¼30.3e32.2 min, m/z 431; 16b: tR¼7.8e8.2 min, m/z 325; 16c: tR¼38.8e39.8 min, m/z 476. For the semi-quantification, the peak areas of the UV traces detected at l¼300 nm were used. For the calculations, additivity of the extinction coefficients, determined with 14 and 2-(4-benzyloxy-2-nitrophenyl)ethanol43 as model compounds, of the several chromophores was assumed: ε¼3.8$103 l mol1 cm1 for compound 14 with two Phth groups (measured value), ε¼1.9$103 l mol1 cm1 estimated for compounds 15a,b and 16a,b with a single Phth group, and ε¼3.3$103 l mol1 cm1 estimated for 15c and 16c with a Phth (ε¼1.9$103 l mol1 cm1) and a nitrobenzene group (ε¼1.4$103 l mol1 cm1). Thus, the peak areas were weighted with the factors of 1.00 (for compound 14), 2.00 (for compounds 15a,b and 16a,b), and 1.15 (for compounds 15c and 16c). The selectivities were calculated individually for each of the six transformations and averaged for the two transformations with the same starting material. The raw data (peak areas) for the six reactions were: 14/15a/ 16a: 1326/115/43 and 3170/314/111; 14/15b/16b: 3003/119/33 and 2089/104/30; 14/15c/16c: 523/9/4 and 397/7/3, which corresponds

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D. Pauli, S. Bienz / Tetrahedron 70 (2014) 1348e1356

to regioselectivities of 80:15:5 (for 6a), 90:8:2 (for 6b), and 97:2:1 (for 6c). 4.4. Methylation/Hofmann eliminations with the model compounds 6c and 12 as proof of principle 4.4.1. N,N 0 -{4-[2-(4-Benzyloxy-2-nitrophenyl)ethyl]-4-methyl-4azoniaoctane-1,8-diyl}bis[phthalimide]iodide (17). Tertiary amine 6c (330 mg, 0.50 mmol) was dissolved in dry DMF (10 ml), and MeI (0.3 ml, 4.8 mmol) was added. The mixture was stirred at 23  C for 3 h, and the volatiles were removed by evaporation. Column chromatography (CH2Cl2/MeOH with a gradient from 100:5 to 100:10) gave quaternary ammonium salt 17 (368 mg, 0.46 mmol, 92%) as a yellow, glassy solid. IR: 2948w, 1770w, 1706s, 1619w, 1529m, 1500w, 1466w, 1438w, 1397m, 1362m, 1251w, 1189w, 1089w, 1024w, 908m, 718s, 644w, 529w. 1H NMR (400 MHz): 7.95 (d, J¼8.6, 1H); 7.80e7.75 (m, 4H); 7.71e7.67 (m, 4H); 7.49 (d, J¼2.7, 1H); 7.41e7.31 (m, 5H); 7.24 (dd, J¼8.6, 2.7, 1H); 5.07 (s, 2H); 3.88e3.69 (m, 10H); 3.47 (s, 3H); 3.40e3.36 (m, 2H); 2.37e2.29 (m, 2H); 1.88 (br s, 4H). 13C NMR (100 MHz): 168.6 (s, 2C); 168.4 (s, 2C); 158.7 (s); 149.2 (s); 135.70 (d); 135.68 (s); 134.4 (d, 2C); 134.3 (d, 2C); 132.0 (s, 2C); 131.9 (s, 2C); 128.9 (d, 2C); 128.6 (d); 127.7 (d, 2C); 123.7 (d, 2C); 123.5 (d, 2C); 121.8 (s); 121.4 (d); 111.7 (d); 70.8 (t); 61.9 (t); 61.7 (t); 60.1 (t); 49.0 (q); 36.6 (t); 35.1 (t); 26.5 (t); 25.8 (t); 22.6 (t); 19.8 (t). ESI-MS: 675 (100, [MI]þ). 4.4.2. N,N 0 -(4-Methyl-4-azaoctane-1,8-diyl)bis[phthalimide] (18). Ammonium iodide 17 (102 mg, 127 mmol) was dissolved in dry CH2Cl2 (10 ml). DBU (38 ml, 254 mmol) was added, and the mixture was stirred at 23  C for 17.5 h. Evaporation of the solvent followed by two column chromatographies (CH2Cl2/MeOH with a gradient of 100:0 to 100:5 and CH2Cl2/MeOH 100:5) gave tertiary amine 18 (42.5 mg, 101 mmol, 80%) as a colorless oil. IR: 2941w, 2855w, 2792w, 1769w, 1702s, 1613w, 1466w, 1437w, 1393s, 1364m, 1335m, 1187w, 1035m, 893w, 795w, 715s, 529m. 1H NMR (500 MHz): 7.84e7.80 (m, 4H); 7.71e7.67 (m, 4H); 3.71 (t, J¼7.3, 2H); 3.68 (t, J¼7.2, 2H); 2.39 (t, J¼7.3, 2H); 2.33 (t, J¼7.3, 2H); 2.16 (s, 3H); 1.82 (quint., J¼7.2, 2H); 1.67 (quint.-like m, J¼ca. 7.5, 2H); 1.45 (quint.-like m, J¼ca. 7.5, 2H). 13C NMR (125 MHz): 168.54 (s, 2C); 168.53 (s, 2C); 133.96 (d, 2C); 133.94 (d, 2C); 132.38 (s, 2C); 132.33 (s, 2C); 123.30 (d, 2C); 123.28 (d, 2C); 57.3 (t); 55.5 (t); 41.9 (q); 38.0 (t); 36.5 (t); 26.6 (t); 26.4 (t); 24.7 (t). ESI-MS: 420 (100, [MþH]þ). HR-MS: calcd for C24H26N3O4 420.19178; found 420.19188. 4.4.3. Di-tert-butyl-N,N0 -{4-[2-(4-benzyloxy-2-nitrophenyl)ethyl]-4methyl-4-azoniaoctane-1,8-diyl}bis[carbamate] iodide (19). Analogous to Section 4.4.1, amine 12 (100 mg, 0.15 mmol) was treated with MeI (0.1 ml, 1.6 mmol) in dry DMF (10 ml) at 23  C for 1.5 h. Column chromatography (CH2Cl2/MeOH 10:1) gave quaternary ammonium salt 19 (100 mg, 0.13 mmol, 86%) as a yellow, glassy solid. IR: 3300w (br), 2976w, 2936w, 2873w, 1694s, 1621w, 1529s, 1454m, 1390w, 1364m, 1345m, 1250s, 1168s, 1014m, 855w, 817w, 781w, 736m, 699w. 1H NMR (300 MHz): 7.83 (d, J¼8.5, 1H); 7.58 (d, J¼2.6, 1H); 7.40e7.30 (m, 5H); 7.23 (dd, J¼8.5, 2.6, 1H); 5.56 (br s, 1H); 5.08 (s overlaying with a br s, 3H); 3.67e3.59 (br m, 6H); 3.38e3.25 (br m overlaying a br s, 7 H); 3.17 (br q, J¼6.0, 2H); 2.15e2.05 (br m, 2H); 1.93e1.81 (br m, 2H); 1.68e1.60 (br m, 2H); 1.38, 1.36 (2s, 18H). 13C NMR (75 MHz): 158.7 (s); 156.5 (s, 2C); 149.2 (s); 135.6 (s); 135.3 (d); 128.8 (d, 2C); 128.5 (d); 127.6 (d, 2C); 121.9 (s); 121.5 (d); 111.6 (d); 79.6 (s); 79.4 (s); 70.8 (t); 62.1 (t); 61.8 (t); 60.5 (t); 48.9 (q); 39.0 (br t); 37.6 (br t); 28.5 (q, 6C); 26.9 (br t); 26.6 (t); 23.4 (t); 19.5 (t). ESI-MS: 615 (100, [MI]þ). 4.4.4. Di-tert-butyl-N,N0 -(4-methyl-4-azaoctane-1,8-diyl)bis[carbamate] (20). Ammonium iodide 19 (50 mg, 67 mmol) was dissolved in CH2Cl2 (0.2 ml) and THF (2.5 ml). tBuOK (1 M in THF, 0.15 ml) was

added, and the mixture was stirred for 15 min. An aq soln of NH4HCO2 (10 M, 0.1 ml) was added, and the mixture was stirred for another 2 min. The volatiles were removed in vacuo, and column chromatography (CH2Cl2/MeOH/NH4OH (25% aq) 100:10:1) gave tertiary amine 20 (22 mg, 61 mmol, 91%) as a colorless oil. Analytical data under Section 4.6.4. 4.5. Synthesis of resin 24 4.5.1. Resin 22. 4-Methyl-3-nitrophenol (7, 4.9 g, 32.1 mmol) was dissolved in dry DMF (300 ml), and the yellow soln was degassed with a stream of Ar for 30 min. NaH (60% dispersion in mineral oil, 1.3 g, 32.5 mmol) was added over a period of 10 min. After the development of H2 was complete, Merrifield resin (21, 10.3 g, 8.3 mmol, loading determined by Volhard titration52) was added, and the mixture was stirred with a mechanical stirrer at 60  C for 48 h. The resin was filtered off, washed sequentially with DMF/ MeOH (1:1), DMF, CH2Cl2, CH2Cl2/MeOH (1:1), and MeOH, and dried in vacuo to give resin 22 (11.0 g). Volhard titration indicated complete transformation. IR: 1530, 1345, 1245, 1025. 4.5.2. Resin 24. Resin 22 (10.4 g) was swelled in dry DMF (250 ml) and DMF-DMA (12 ml, 90 mmol) and pyrrolidine (7 ml, 85 mmol) were added. The mixture was stirred with a mechanical stirrer and heated to 100  C for 48 h, then allowed to cool to 23  C. The resin was filtered off, washed sequentially with DMF, CH2Cl2, CH2Cl2/ MeOH (1:1), MeOH, and CH2Cl2, and dried in vacuo. The thus obtained dark purple resin 23 was swelled in CH2Cl2 (200 ml), and an aq HCl soln (10%, 100 ml) was added. The mixture was vigorously stirred with a mechanical stirrer for 4 h at 40  C before the resin was filtered off and washed sequentially with HCl (10% aq)/DMF (1:3), DMF, DMF/MeOH (1:1), MeOH, CH2Cl2, CH2Cl2/MeOH (1:1), and MeOH, and dried in vacuo to give resin 24 (10.5 g). IR: 1728, 1692, 1529. 4.6. Determination of the loading of resin 24 4.6.1. Via resin 25 through oxidation/Cope eliminationdresin 25. Resin 24 (500 mg) was swelled in dry DCE (5 ml). Bis[phthalimide] 544 (540 mg, 1.33 mmol) was added, and the mixture was agitated at 23  C for 1 h before NaBH(OAc)3 (285 mg, 1.34 mmol) was added. After 10 min, AcOH (70 ml, 1.22 mmol) was added, and the mixture was agitated for an additional 2.5 h. MeOH (5 ml) was added and the mixture as agitated for an additional 5 min. Then, the resin was filtered off and washed sequentially with MeOH, DMF/ AcOH (100:1), DMF/DIEA (10:1), CH2Cl2, CH2Cl2/MeOH (1:1), and MeOH. Drying in vacuo delivered resin 25, which was used in the next step without further treatment. IR: 1771, 1711, 1528. 4.6.2. N,N 0 -(4-Hydroxy-4-azaoctane-1,8-diyl)bis[phthalimide] (14). Resin 25 from above was swelled in dry CH2Cl2 (5 ml), and the mixture was agitated for 15 min while the suspension was cooled to 0  C. m-CPBA (77%, 240 mg, 1.07 mmol) was added and the mixture was agitated at 0  C for 2.5 h. The resin was filtered off and washed sequentially with ice-cooled CH2Cl2, MeOH, CH2Cl2/MeOH (1:1), and CH2Cl2. After drying in vacuo, the resin was swelled in toluene (10 ml) and heated to 90  C for 2 h. The mixture was allowed to cool to 23  C and filtered, and the resin was rinsed with toluene, CH2Cl2, and MeOH. The filtrate and the rinsing solns were combined and the solvents were evaporated in vacuo. Column chromatography (CH2Cl2/MeOH 100:1.5) delivered hydroxylated triamine 14 (60 mg, 142 mmol) as a colorless solid. The functional loading capacity of resin 24, based on this model reaction, thus, amounts to 0.284 mmol g1. UV (H2O/MeCN/TFA 60:40:0.1): lmax 300 (3.8$103 l mol1 cm1). IR: 3463w (br), 2941w, 2867w, 1769w, 1701s, 1613w, 1465w, 1438w, 1395s, 1363m, 1335m, 1186w, 1171w,

D. Pauli, S. Bienz / Tetrahedron 70 (2014) 1348e1356

1029w, 892w, 795w, 715s, 623w, 529m. 1H NMR (600 MHz): 7.85e7.81 (m, 4H); 7.72e7.67 (m, 4H); 3.80 (t, J¼7.1, 2H); 3.72 (t, J¼7.1, 2H); 2.69 (t, J¼6.5, 2H); 2.65 (t, J¼6.8, 2H); 1.96 (quint., J¼6.7, 2H); 1.72 (quint., J¼7.2, 2H); 1.57 (quint., J¼7.2, 2H). 13C NMR (150 MHz): 168.70 (s, 2C); 168.68 (s, 2C); 134.03 (d, 2C); 134.00 (d, 2C); 132.33 (s, 2C); 132.28 (s, 2C); 123.34 (d, 2C); 123.32 (d, 2C); 60.5 (t); 58.2 (t); 38.1 (t); 36.2 (t); 26.6 (t); 26.4 (t); 24.4 (t). ESI-MS: 444 (100, [MþNa]þ); 422 (58, [MþH]þ); 404 (10); 257 (13). HR-MS: calcd for C23H23N3NaO5 444.15299; found 444.15305. 4.6.3. Via resin 26 through methylation/Hofmann eliminationdresin 26. Analogous to Section 4.6.1, aldehyde resin 24 (500 mg) was treated with bis[carbamate] 1151 (476 mg, 1.38 mmol) and NaBH(OAc)3 (285 mg, 1.34 mmol) to give resin 26, which was used in the next step without further treatment. IR: 1711, 1528, 1247, 1167.

1355

(10:1), CH2Cl2, CH2Cl2/MeOH (1:1), and MeOH, and dried in vacuo. Chloranil-test54 negative. IR: 1711, 1528, 1347, 1167. 4.7.3. tert-Butyl-N-[4-hydroxy-8-(2-nitrobenzenesulfonylamino)-4azaoctyl]carbamate (31). Analogous to Section 4.6.2, hydroxylamine 31 was cleaved from resin 30 (142 mmol) by oxidation with m-CPBA (1.07 mmol) and heating to 90  C in toluene. Column chromatography (CH2Cl2/MeOH/NH4OH (25% aq) 100:5:0.5) delivered 31 (44 mg, 98 mmol, 69%) as a colorless oil. IR: 3349w (br), 2935w, 2871w, 1687m, 1540s, 1444w, 1412w, 1364m, 1341m, 1274m, 1251m, 1165s, 1082w, 854w, 782w, 737m, 656w, 588m. 1H NMR (500 MHz): 8.15e8.10 (m, 1H); 7.83e7.80 (m, 1H); 7.75e7.69 (m, 2H); 6.40 (br s, 1H); 4.90 (br s, 1H); 3.19 (br q, J¼6.0, 2H); 3.11e3.09 (m, 2H); 2.70 (t, J¼6.8, 2H); 2.63 (t, J¼6.0, 2H); 1.78 (quint., J¼6.8, 2H); 1.66e1.61 (m, 4H); 1.42 (s, 9H). 13C NMR (125 MHz): 156.3 (s); 148.1 (s); 133.9 (s); 133.5 (d); 132.8 (d); 131.3 (d); 125.2 (d); 79.2 (s); 60.2 (t); 58.4 (br t); 43.7 (t); 38.9 (br t); 28.5 (q, 3C); 27.9 (t); 27.4 (br t); 24.3 (t). ESI-MS: 469 (100, [MþNa]þ). HR-MS: calcd for C18H30N4NaO7S 469.17274; found 469.17237.

4.6.4. Di-tert-butyl-N,N0 -(4-methyl-4-azaoctane-1,8-diyl)bis[carbamate] (20). Resin 26 from above was swelled in dry DMSO (5 ml). MeI (0.3 ml, 4.8 mmol) was added and the mixture was agitated at 23  C for 20 h. The resin was filtered off, washed sequentially with DMF, DMF/CH2Cl2 (1:1), CH2Cl2, MeOH, CH2Cl2/MeOH (1:1), and CH2Cl2, and dried in vacuo. The such obtained resin was swelled in dry THF (5 ml), tBuOK (1 M in tBuOH, 0.5 ml, 0.5 mmol) was added, and the mixture was agitated at 23  C for 15 min. The excess of base was quenched with an aq soln of NH4HCO2 (10 M, 0.15 ml), THF (5 ml), and MeOH (5 ml) were added, and the mixture was agitated for an additional 5 min. The mixture was filtered, and the resin was rinsed with THF, CH2Cl2, and MeOH. The filtrate and rinsing solns were combined, and the solvent was evaporated in vacuo. Column chromatography (CH2Cl2/MeOH/NH4OH (25% aq) 100:10:1) gave tertiary amine 20 (51 mg, 142 mmol) as a colorless oil. The functional loading capacity of resin 24, based on this model reaction, thus, amounts to 0.284 mmol g1. IR: 3337w (br), 2973w, 2934w, 2868w, 2794w, 1689s, 1520m, 1454m, 1390w, 1365m, 1271m, 1250s, 1169s, 1042w, 867w, 780w, 642w. 1H NMR (500 MHz): 5.39 (br s, 1H); 4.95 (br s, 1H); 3.16e3.07 (m, 4H); 2.36 (t, J¼6.8, 2H); 2.32e2.29 (m, 2H); 2.15 (s, 3H); 1.62 (quint., J¼6.6, 2H); 1.49e1.46 (m, 4H); 1.40 (s, 18H). 13C NMR (125 MHz): 156.2 (s); 156.1 (s); 79.0 (s); 78.9 (s); 57.3 (t); 56.3 (t); 41.8 (q); 40.5 (t); 39.9 (t); 28.54 (q); 28.52 (q); 27.8 (t); 26.9 (t); 24.6 (t). ESI-MS: 360 (100, [MþH]þ). HR-MS: calcd for C18H38N3O4 360.28568; found 360.28549.

4.7.4. tert-Butyl-N-[4-methyl-8-(2-nitrobenzenesulfonylamino)-4azaoctyl]carbamate (32). Analogous to Section 4.6.4, tertiary amine 32 was cleaved from resin 30 (142 mmol) by methylation with MeI (4.8 mmol) and treatment with tBuOK (0.5 mmol). Column chromatography (CH2Cl2/MeOH/NH4OH (25% aq) 100:7:0.7) delivered 32 (47 mg, 106 mmol, 75%) as a colorless oil. IR: 3352w (br), 2937w, 2867w, 2798w, 1691m, 1541s, 1456w, 1365m, 1339m, 1275w, 1251m, 1164s, 1127m, 1079w, 1061w, 852w, 782m, 741m, 654w, 586m. 1H NMR (500 MHz): 8.11e8.09 (m, 1H); 7.77e7.76 (m, 1H); 7.72e7.68 (m, 2H); 5.07 (br t, J¼4.9, 1H); 3.14 (q, J¼6.2, 2H); 3.04 (t, J¼6.2, 2H); 2.42 (t, J¼7.2, 2H); 2.34 (t, J¼6.2, 2H); 2.19 (s, 3H); 1.69 (quint., J¼7.0, 2H); 1.62e1.52 (m, 4H); 1.41 (s, 9H). 13C NMR (125 MHz): 156.2 (s); 148.2 (s); 134.1 (s); 133.3 (d); 132.5 (d); 131.0 (d); 125.0 (d); 79.0 (s); 57.2 (t); 55.7 (t); 43.5 (t); 41.4 (q); 39.4 (t); 28.5 (q, 3C); 28.3 (t); 26.8 (t); 24.8 (t). ESI-MS: 467 (8, [MþNa]þ); 445 (100, [MþH]þ); 360 (11); 173 (6). HR-MS: calcd for C19H33N4O6S 445.21153; found 445.21106.

4.7. Stepwise construction of triamine derivatives on solid support

Supplementary data

4.7.1. Resin 28. Resin 24 (500 mg, 142 mmol) was swelled in dry DCE (5 ml). 4-Aminobutylsulfonamide 2747 (344 mg, 1.26 mmol) was added, and the mixture was agitated at 23  C for 1 h. NaBH(OAc)3 (273 mg, 1.29 mmol) was added, and the resulting mixture was again shaken. After 5 min, AcOH (70 ml, 1.22 mmol) was added, and the suspension was agitated for an additional 2 h. MeOH (5 ml) was added, and the mixture was agitated for 5 min before the resin was filtered, sequentially washed with MeOH, DMF/AcOH (100:1), DMF/Et3N (100:5), CH2Cl2, and MeOH, and dried in vacuo. IR: 1528, 1345, 1166. 4.7.2. Resin 30. Resin 28 (142 mmol) was swelled in dry DCE (5 ml), and 3-(tert-butylcarboxylamino)propanal53 (29, 224 mg, 1.29 mmol) was added. The mixture was agitated at 23  C for 1 h, NaBH(OAc)3 (302 mg, 1.42 mmol) was added, and, after 10 min of agitation, AcOH (70 ml, 1.22 mmol). The mixture was agitated for an additional 2 h. MeOH (5 ml) was added and the mixture was agitated for an additional 5 min before the resin was filtered, sequentially washed with MeOH, DMF/AcOH (100:1), DMF/Et3N

Acknowledgements We would like to thank Silvan Eichenberger for the HPLC quantifications and the Swiss National Science Foundation for their generous financial support.

The 1H and 13C NMR spectra of all new non-resin-bound products are available. Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/ j.tet.2013.12.014. These data include MOL files and InChiKeys of the most important compounds described in this article. References and notes ^a, A. G. J. Braz. 1. Eifler-Lima, V. L.; Graebin, C. S.; Uchoa, F. D. T.; Duarte, P. D.; Corre Chem. Soc. 2010, 21, 1401e1423. 2. Hone, N. D.; Payne, L. J. Tetrahedron Lett. 2000, 41, 6149e6152. 3. Nash, I. A.; Bycroft, B. W.; Chan, W. C. Tetrahedron Lett. 1996, 37, 2625e2628. 4. Strømgaard, K.; Andersen, K.; Ruhland, T.; Krogsgaard-Larsen, P.; Jaroszewski, J. W. Synthesis 2001, 877e884. 5. Strømgaard, K.; Bjørnsdottir, I.; Andersen, K.; Brierley, M. J.; Rizoli, S.; Eldursi, N.; Mellor, I. R.; Usherwood, P. N. R.; Hansen, S. H.; Krogsgaard-Larsen, P.; Jaroszewski, J. W. Chirality 2000, 12, 93e102. 6. Strømgaard, K.; Brier, T. J.; Andersen, K.; Mellor, I. R.; Saghyan, A.; Tikhonov, D.; Usherwood, P. N. R.; Krogsgaard-Larsen, P.; Jaroszewski, J. W. J. Med. Chem. 2000, 43, 4526e4533. 7. Wang, F.; Manku, S.; Hall, D. G. Org. Lett. 2000, 2, 1581e1583. 8. Strømgaard, K.; Jensen, L. S.; Vogensen, S. B. Toxicon 2005, 45, 249e254. 9. Strømgaard, K.; Mellor, I. Med. Res. Rev. 2004, 24, 589e620.

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