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

Article abstract of DOI:10.1016/j.tet.2013.12.014

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 respectiv

Full text of DOI:10.1016/j.tet.2013.12.014

Tetrahedron 70 (2014) 1348e1356
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Development of a new linker for the solid-phase synthesis of
N-hydroxylated and N-methylated secondary amines
*
Denise Pauli, Stefan Bienz
€
Institute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
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.
Keywords:
Solid-phase synthesis
Linker
Ó 2013 Elsevier Ltd. All rights reserved.
N-Hydroxylation
N-Methylation
Secondary amine
Spider toxin
Cope elimination
Hofmann elimination
1. Introduction
are, for instance, the toxins LF448A21 and AG432g22 from Lar-
inioides folium and Agelenopsis aperta, respectively (Fig. 1).
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 syn-
thesize 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 acyla-
tion, 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
O
H
N
H
N
NH2
N
H
N
O
Me
N
H
CONH2
LF448A
OH
H
N
H
N
H
N
N
NH2
O
N
H
AG432g
Fig. 1. Representative structures of N-hydroxylated and N-methylated spider toxins.
Since the structures of N-methylated and N-hydroxylated poly-
amine spider toxins are closely related to each other, access to
common intermediates in their preparationwould 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,
* Corresponding author. Tel.: þ41 44 635 42 45; fax: þ41 44 635 68 12; e-mail
addresses: sbienz@oci.uzh.ch, stefan.bienz@uzh.ch (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

D. Pauli, S. Bienz / Tetrahedron 70 (2014) 1348e1356
1349
allowed proper control of the reaction conditions and appropriate
analysis of the products. As the model compounds, the three phe-
nethyl bromides 4aec were selected. While compound 4a repre-
sents 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 sub-
strate, carrying neither a donating (alkoxy) nor an accepting (nitro)
group.
R2
N
R2
N
base
AG
n
AG
AG
R1
o
i
–
–
t
a
Me
HO
R1
l
y
h
Me
R2
N
t
e
a
m
r
e
p
B
D
AG
R1
o
x
i
d
t
i
o
n
R2
N
R2
N
A
R1
R1
AG
O
The three bromides 4aec43 were treated with bis-phthal-
protected spermidine 544 in the presence of NaI and diisopropyle-
thylamine (DIEA) to deliver the corresponding tertiary amines 6aec
in 46, 36, and 8% yields, respectively (Scheme 2). While the re-
actions of 4a and 4b were rather slow, not coming to completion in
120 h at 50ꢀ, the substitution reaction with 4c was problematic
with regards to a side reaction: it was accompanied by the elimi-
nation of HBr, which delivered the respective styrene product in
a yield of as high as 55%.
C
E
activation by carboxyl
O
R2
N
H
H
H
O
R1
O
O
1
activation by aryl
R1
N
H
Br
R2
O
R
O
R
NPhth
2
3
R = H
R = NO2
NPhth
NPhth
HN
NPhth
Br
N
5
Scheme 1.
R1
R2
R1
R2
NaI, DIEA, DMF
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
4a R1 = BnO R2 = H
6a R1 = BnO R2 = H
(46%)
(36%)
(8%)
4b R1 = H
R2 = H
4c R1 = BnO R2 = NO2
6b R1 = H
R2 = H
6c R1 = BnO R2 = NO2
Scheme 2.
The problem of HBr-elimination was overcome by using alde-
hyde 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 pres-
ence of base afforded in the initial step O-benzyl-protected de-
rivative 8 (93%). This compound delivered enamine 9 upon its
treatment with N,N-dimethyl formamide dimethyl acetal (DMF-
DMA) 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 NaB-
H(OAc)3 in presence of AcOH46 delivered 6c and its bis-Boc-
protected analog 12 in 86% and 62% yield.
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 effi-
ciently, the oxidation/Cope elimination process, however, proved
less suitable.41 Due to the strong activation of the H atoms in
a-
position 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 N-
methylated 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 re-
action 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 mole-
cule. 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.
N(H)PG
Me
N
N(H)PG
RO
NO2
BnO
NO2
7
R = H
R = Bn (93%)
6c N(H)PG = NPhth (86%)
12 N(H)PG = NHBoc (62%)
BnBr, K2CO3
DMF
8
N(H)PG
DMF-DMA
pyrrolidine
DMF
NaBH(OAc)3
HN
N(H)PG
AcOH
ClCH2CH2Cl
5
N(H)PG = NPhth
N(H)PG = NHBoc
11
N
HCl (10% aq.)
CHO
NO2
CH2Cl2
BnO
NO2
BnO
9
10 (76%)
Scheme 3.
2. Results and discussion
To test the influence of the linker moieties on the regiose-
lectivities 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
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

1350
D. Pauli, S. Bienz / Tetrahedron 70 (2014) 1348e1356
NPhth
NPhth
NPhth
NPhth
N
O
HO
+
N
R1
R2
14
R1
R2
13a–13c
NPhth
+
N
OH
NPhth
NPhth
R1
R2 15a–15c
Ratios:
+
a: R1 = BnO R2 = H
b: R1 = H R2 = H
14:15a:16a 80:15: 5
14:15b:16b 90: 8: 2
OH
N
NPhth
c: R1 = BnO R2 = NO2 14:15c:16c 97: 2: 1
R1
R2
16a–16c
Scheme 4.
acidic byproduct, the N-oxides were heated in toluene to 90ꢀ 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 chromo-
phores and their extinction coefficients at 300 nm into account.
From the results summarized in Scheme 4 it is readily recog-
nized 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.
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 com-
pound 19, the bis-N-Boc analog of 17, which was obtained by per-
methylation of tertiary amine 12. Treatment of 19 with BuOK in
CH2Cl2 for 15 min delivered the desired amine 20 in excellent 91%
yield.
t
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 analo-
gously 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 gꢁ1). 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.
To study the potential of the new linker for the synthesis of N-
methylated 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.
Me
Me
NaH
DMF
+
O
NO2
Cl
HO
NO2
N(H)PG
Me
21
7
22
N
N(H)PG
base
N(H)PG
N(H)PG
DMF-DMA
pyrrolidine
DMF
N
BnO
NO2
Me
17 N(H)PG = NPhth (92%)
19 N(H)PG = NHBoc (86%)
18 N(H)PG = NPhth (<80%)
20 N(H)PG = NHBoc (91%)
N
CHO
HCl (10% aq.)
CH2Cl2
Scheme 5.
O
NO2
O
NO2
24
23
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]oc-
tane) with estimated pKa values for the conjugate acids in DMSO of
8.5 and 8.9, respectively. With the stronger amidine base DBU (1,6-
diazabicyclo[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
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 re-
actions 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
N
N(H)PG
oxididation/
Cope elimination or
1. 5 or 11
ClCH2CH2Cl
CHO
NO2
(1.0 g)
N(H)PG
N(H)PG
N
O
O
NO2
X
methylation/
Hofmann elimination
2. NaBH(OAc)3
AcOH
24
25
14
N(H)PG = NPhth
N(H)PG = NHBoc
N(H)PG = NPhth X = HO (0.284 mmol)
N(H)PG = NHBoc X = Me (0.284 mmol)
26
20
Scheme 7.
t
treated with BuOK 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 ca-
pacity of the resin.
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 termi-
nal 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 labo-
rious, 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 cho-
sen 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 ami-
nation 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/Hof-
mann elimination, finally, released the N-hydroxylated and N-
methylated 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.
The superiority of the new resin 24 over Seo’s resin 2 for the
preparation of N-hydroxylated polyamines can be well demon-
strated 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
(d
¼5e6 ppm) and the signals at approximately ¼4.3 and 3.5 ppm
d
of spectrum (b) indicate the formation of considerable amounts of
olefinic side products, derived from Cope elimination towards the
undesired sites of the molecule.
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
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.
NHNs
NHNs
NH
NH 27
1.
CHO
NO2
ClCH2CH2Cl
O
O
NO2
O
2. NaBH(OAc)3
AcOH
24
28
NHBoc
29
1.
2.
ClCH2CH2Cl
NaBH(OAc)3
AcOH
NHNs
NHBoc
N
oxid./Cope elim. or
NHNs
N
NHBoc
meth./Hofmann elim.
O
NO2
X
30
31 X = HO (69%)
32 X = Me (75%)
Scheme 8.

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, per-
formed with a shorter and, thus, sterically more hindered prop-
andiamine derivative, delivered substantially less of the desired
product.
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 mlꢁ1) were continuously
introduced through the electrospray interface with a syringe in-
fusion pump (Cole-Parmer 74900-05) at a flow rate of 3 m
l minꢁ1. 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 ꢂ5 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.
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 at-
tached to the resins by reductive amination, but the reaction is
more efficient for secondary amines. For the preparation of un-
symmetrically, orthogonally protected triamine intermediates, the
choice between optimized yields and ease of procedures has to be
made.
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 chromatog-
raphy (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. Experimental
4.1. General
Starting materials were purchased from commercial suppliers
and used without further purification. For NaBH(OAc)3, it was nec-
essary to shrunk the clots before usage. All reactions in solutionwere
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 dis-
tilled 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 gꢁ1 loading (Advanced ChemTech). UV spectra: Cary Se-
ries 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’ spectropho-
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).
tometer. The wavenumbers (1/l
) are given in cmꢁ1 (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 (
given in parts per million relative to peaks of residual solvents CHCl3
(for 1H: 7.26 ppm; for 13C: 77.16 ppm). The coupling constants J are
d) are
d
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 mea-
sured 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. Per-
fluorokerosene (Fluorochem) served for calibration. ESI-MS mea-
surements were performed on a Bruker ESQUIRE-LC quadrupole ion
trap instrument (Bruker Daltonik GmbH), equipped with a com-
bined HewlettePackard Atmospheric Pressure Ion (API) source. The
4.2.3. N,N0-{4-[2-(4-Benzyloxy-2-nitrophenyl)ethyl]-4-azaoctane-
1,8-diyl}bis[phthalimide] (6c)dby substitution of 2-(4-benzyloxy-2-
nitrophenyl)ethyl bromide (4c). Analogous to Section 4.2.1, bis
[phthalimide] 544 (2.24 g, 5.50 mmol) was reacted with 2-(4-
benzyloxy-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
solns (about 0.1e1
through the electrospray interface with a syringe infusion pump
(Cole-Parmer 74900-05) at a flow rate of 5
l minꢁ1. The MS ac-
quisitions wereperformed at normal resolution (>1000 full width at
m
mol mlꢁ1) were continuously introduced
m

D. Pauli, S. Bienz / Tetrahedron 70 (2014) 1348e1356
1353
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 ad-
dition of a satd aq soln of NaHCO3. The organic layer was washed
with a satd aq soln of NaHCO3 and with brine. Column chromatog-
raphy (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).
13C 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).
aldehyde 10 (457 mg, 1.68 mmol) was condensed with bis[carba-
mate] 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
4.2.4. 4-Benzyloxy-2-nitrotoluene (8, prepared analogous to
Ref. 50). 4-Methyl-3-nitrophenol (7, 13.80 g, 90.1 mmol) was dis-
solved 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
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 sol-
vents 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.
ꢃ
(q). EI-MS: 243 (3, Mþ ), 213 (2, [MꢁNO]þ), 91 (100, [C7H7]þ), 77 (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 HPLC-
[C6H5]þ), 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.
UV(DAD)-ESI-MS, using
(250ꢄ4.6 mm) under reversed-phase conditions with H2O/MeCN/
TFA 60:40:0.1 (isocratic) as the eluent at a flow rate of 1 ml minꢁ1
a
Kromasil K100 10C18 column
4.2.5. 2-(4-Benzyloxy-2-nitrophenyl)ethanal (10, prepared analo-
gous 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 (DMF-
DMA, 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
.
The analytes were identified by their [MþH]þ ion responses in ESI-
MS: 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
l
¼300 nm were used. For
the calculations, additivity of the extinction coefficients, de-
termined with 14 and 2-(4-benzyloxy-2-nitrophenyl)ethanol43 as
model compounds, of the several chromophores was assumed:
ε¼3.8$103 l molꢁ1 cmꢁ1 for compound 14 with two Phth groups
(measured value), ε¼1.9$103 l molꢁ1 cmꢁ1 estimated for com-
pounds 15a,b and 16a,b with
a single Phth group, and
ε¼3.3$103 l molꢁ1 cmꢁ1 estimated for 15c and 16c with a Phth
(ε¼1.9$103
l
molꢁ1 cmꢁ1
)
and
a
nitrobenzene group
(ε¼1.4$103 l molꢁ1 cmꢁ1). 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 ma-
terial. 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
ꢃ
(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]-4-
azaoctane-1,8-diyl}bis[carbamate] (12). Analogous to Section 4.2.3,

1354
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).
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
4.4. Methylation/Hofmann eliminations with the model
compounds 6c and 12 as proof of principle
tertiary amine 20 (22 mg, 61 mmol, 91%) as a colorless oil. Analytical
data under Section 4.6.4.
4.4.1. N,N0-{4-[2-(4-Benzyloxy-2-nitrophenyl)ethyl]-4-methyl-4-
azoniaoctane-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, [MꢁI]þ).
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 ob-
tained 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.
4.4.2. N,N0-(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 l, 254
m
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.
4.6. 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[phtha-
limide] 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.
4.4.3. Di-tert-butyl-N,N0-{4-[2-(4-benzyloxy-2-nitrophenyl)ethyl]-4-
methyl-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 quater-
nary 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, [MꢁI]þ).
4.6.2. N,N0-(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
4.4.4. Di-tert-butyl-N,N0-(4-methyl-4-azaoctane-1,8-diyl)bis[carba-
0.284 mmol gꢁ1
. UV (H2O/MeCN/TFA 60:40:0.1): lmax 300
mate] (20). Ammonium iodide 19 (50 mg, 67
m
mol) was dissolved
(3.8$103 l molꢁ1 cmꢁ1). IR: 3463w (br), 2941w, 2867w, 1769w,
in CH2Cl2 (0.2 ml) and THF (2.5 ml). tBuOK (1 M in THF, 0.15 ml) was
1701s, 1613w, 1465w, 1438w, 1395s, 1363m, 1335m, 1186w, 1171w,

D. Pauli, S. Bienz / Tetrahedron 70 (2014) 1348e1356
1355
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.
(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)-4-
azaoctyl]carbamate (31). Analogous to Section 4.6.2, hydroxyl-
amine 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) de-
livered 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.
4.6.3. 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 NaB-
H(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.
4.6.4. Di-tert-butyl-N,N0-(4-methyl-4-azaoctane-1,8-diyl)bis[carba-
mate] (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)
4.7.4. tert-Butyl-N-[4-methyl-8-(2-nitrobenzenesulfonylamino)-4-
azaoctyl]carbamate (32). Analogous to Section 4.6.4, tertiary amine
32 was cleaved from resin 30 (142 mmol) by methylation with MeI
t
(4.8 mmol) and treatment with BuOK (0.5 mmol). Column chro-
matography (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
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 gꢁ1. 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.
C19H33N4O6S 445.21153; found 445.21106.
Acknowledgements
We would like to thank Silvan Eichenberger for the HPLC
quantifications and the Swiss National Science Foundation for their
generous financial support.
4.7. Stepwise construction of triamine derivatives on solid
support
Supplementary data
The 1H and 13C NMR spectra of all new non-resin-bound prod-
ucts 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.
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. NaB-
H(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.
References and notes
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