Renewable rigid diamines: Efficient, stereospecific synthesis of high purity isohexide diamines

Article abstract of DOI:10.1002/cssc.201100398

We report an efficient three-step strategy for synthesizing rigid, chiral isohexide diamines derived from 1,4:3,6-dianhydrohexitols. These biobased chiral building blocks are presently the subject of several investigations (in our and several other groups

Full text of DOI:10.1002/cssc.201100398

DOI: 10.1002/cssc.201100398
Renewable Rigid Diamines: Efficient, Stereospecific
Synthesis of High Purity Isohexide Diamines
Shanmugam Thiyagarajan,[a, b] Linda Gootjes,[a, b] Willem Vogelzang,[a, b]
Jacco van Haveren,[a, b] Martin Lutz,[c] and Daan S. van Es*[a, b]
We report an efficient three-step strategy for synthesizing
rigid, chiral isohexide diamines derived from 1,4:3,6-dianhydro-
hexitols. These biobased chiral building blocks are presently
the subject of several investigations (in our and several other
groups) because of their application in high-performance bio-
based polymers, such as polyamides and polyurethanes.
Among the three possible stereo-isomers, dideoxy-diamino iso-
idide and dideoxy-diamino isosorbide can be synthesized from
isomannide and isosorbide respectively in high yield with ab-
solute stereo control. Furthermore, by using this methodology
dideoxy-amino isomannide—a tricyclic adduct—was obtained
starting from isoidide in high yield. Our improved synthetic
route is a valuable advance towards meeting scale and purity
demands for evaluating the properties of new biobased perfor-
mance materials, which will benefit the development of these
plastics.
Introduction
Biobased polymers are an increasingly important field in both
academic research and industrial development, owing to the
growing awareness that sustainability and the use of renewa-
ble feedstocks are key factors for future economic growth.
Rapidly depleting fossil fuel reserves, as well as the disruptive
effects of global warming caused by greenhouse gas emis-
sions, are among the more prominent drivers in this process.
The efficient use of renewable biobased feedstocks for the pro-
duction of high performance synthetic materials is one way to
address these issues.
The parent isohexides (diols) have also served as the starting
material in the synthesis of a variety of analogous, rigid, bicy-
clic building blocks.[3] Of particular interest to our work on bio-
based polymers is the class of dideoxy-diamino isohexides;
which serve as rigid, renewable building blocks in, for example,
biobased polyamides and polyurethanes.
Thiem et al. were the first to describe the use of these chiral
diamines in the synthesis of polyurethanes and polyamides.[4]
Recently, the use of high purity dideoxy-diamino isoidide in
the preparation of a series of fully biobased semicrystalline
polyamides by means of melt/interfacial polycondensation was
reported.[5a] Moreover, the increasing amount of patent appli-
cations published on this subject is indicative of the industrial
relevance of these biobased rigid diamines.[5b–d]
Whereas nature provides a plethora of polyols in the form of
carbohydrates, industrially important amines, especially dia-
mines, are far less available. To obtain biobased diamines for
high performance polymer applications, such as polyamides
and polyurethanes, efficient chemical transformations must be
developed. Furthermore, in order to be applied in high perfor-
mance polymers, very high purity (>99.9%) of the building
blocks is required, which requires highly specific chemical
transformations. An especially interesting class of amine build-
ing blocks for high performance polymers are the bicyclic, con-
formationally restricted, diamines.[1a] Among the wide variety
of known biobased monomers only a few can be considered
conformationally restricted or rigid. The family of 1,4:3,6-dia-
nhydrohexitols, also known as isohexides, have proven to be
excellent building blocks for the production of high perfor-
mance biobased polymers, owing to their intrinsic rigidity.[1b–i]
These sugar based diols exist as three different stereoisomers:
1,4:3,6-dianhydro-d-glucidol (isosorbide), 1,4:3,6-dianhydro-d-
mannitol (isomannide), and 1,4:3,6-dianhydro-l-iditol (isoidide),
derived from d-glucose, d-mannose, and l-fructose, respective-
ly. All three isohexides have been extensively studied as mono-
mers in the synthesis of high Tg polymers, such as polyesters
and polycarbonates.[2]
There are only a few reports in the literature describing the
synthesis of unsubstituted dideoxy-diamino isohexides. Most
of these routes suffer from significant drawbacks, such as low
overall yields of purified diamine (<15%)[6,7] or the use of
[a] Dr. S. Thiyagarajan, L. Gootjes, W. Vogelzang, Dr. J. van Haveren,
Dr. D. S. van Es
Food & Biobased Research
Wageningen University & Research Centre
P.O. Box 17, 6700 AA Wageningen (The Netherlands)
Fax: (+31)317 483011
E-mail: daan.vanes@wur.nl
[b] Dr. S. Thiyagarajan, L. Gootjes, W. Vogelzang, Dr. J. van Haveren,
Dr. D. S. van Es
Dutch Polymer Institute
P.O. Box 902, 5600 AX, Eindhoven (The Netherlands)
[c] Dr. M. Lutz
Bijvoet Center for Biomolecular Research
Crystal and Structural Chemistry, Utrecht University
Padualaan 8, 3584, Utrecht (The Netherlands)
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201100398.
ChemSusChem 2011, 4, 1823 – 1829
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1823

D. S. van Es et al.
highly explosive intermediates.[8,9] Driven by our interest in
resin grade dideoxy-diamino isohexides for polymer synthesis,
we have recently reported an improved four-step stoichiomet-
ric route to dideoxy-diamino isoidide, giving the stereoisomer
in 47% isolated yield and 99.9% purity.[10] Recently, the group
of Beller published an elegant, highly efficient, direct catalytic
conversion of isosorbide to dideoxy-diamino isohexides using
ammonia.[11] Although a breakthrough from a green-chemistry
point of view, this procedure also suffers drawbacks. Whereas
high conversions are reported, unfortunately no isolated yields
are given, nor the composition of the mixture of three di-
deoxy-diamino isohexides isomers obtained. Separation of
these isomers, required for application in high performance
polymers, is nontrivial, and can have detrimental effects on iso-
lated yields.
amines.[13] Hence, isosorbide bistosylate 2b and isomannide
bistosylate 2c were reacted with an excess of benzyl amine at
1608C for 24 h under nitrogen atmosphere, resulting in the in-
version of the configuration at the C2 and C5 positions to
afford the isoidide 3a and isosorbide 3b benzyl protected dia-
mines, respectively, (Scheme 1) in almost quantitative yield. Re-
markably, despite the relatively high temperature and the pres-
ence of a base (benzyl amine), side reactions (e. g. elimination)
occurred only to a limited extent, which is reflected in the
high isolated yield and limited discoloration of the product. Re-
moval of the excess benzyl amine under reduced pressure, fol-
lowed by precipitation of the benzylammonium tosylate salts
from an appropriate organic solvents, such as diethyl ether,
yielded the crude product in satisfactory purity (>90% from
NMR and GC analysis).
In continuation of our previous work, we have developed a
new, facile and scalable three-step route to obtain high purity
dideoxy-diamino isohexides with absolute stereocontrol. Our
synthetic strategy encompasses three steps: transformation of
the hydroxyl functionalities into efficient leaving groups, fol-
lowed by nucleophilic substitution with a protected amine,
and finally, catalytic removal of the protecting group, yielding
the free amine.
High purity product was obtained by short path distillation
using a Kugelrohr oven at 200–2258C at 50 mbar for 1 h. As
our goal was to develop an efficient, robust process that re-
quires a minimal amount of purification steps, the subsequent
deprotection of the bisbenzyl amines was performed on the
crude products. Thus, catalytic hydrogenolysis of 3a and 3b
was carried out in ethanol in the presence of Pearlman’s cata-
lyst, Pd(OH)2/C, under 10 bar hydrogen pressure at 508C for
6 h, yielding the corresponding dideoxy-isohexide diamines 4a
and 4b. The crude products were purified by recrystallization
from an ethanol/methanol mixture (2:0.5) to afford >90% off-
white crystalline solids with high purity (99% based on NMR
and GC analysis). Hence, our three-step synthetic strategy,
starting from the parent isohexides, allows for an unprecedent-
ed >80% overall isolated yield of high purity, dideoxy-diamino
isoidide 4a and dideoxy-diamino isosorbide 4b with absolute
stereocontrol.
During the preparation of this manuscript, a patent applica-
tion was published, which describes the synthesis of dideoxy-
diamino isoidide in a similar manner.[12] Since our intention is
to develop novel, scalable procedures to synthesize all three
possible isohexide diamine isomers in high yield and purity, we
present here the convenient and scalable route for the synthe-
sis of dideoxy-diamino isohexides.
Results and Discussion
Our strategy was, unfortunately, ineffective in obtaining the
diamino isomannide derivative. Whereas isosorbide bistosylate
2b and isomannide bistosylate 2c gave the expected SN2
amine products (isosorbide and isoidide configurations, respec-
tively), isoidide bistosylate 2a gave the tricyclic product 3c
with high specificity from the reaction with benzyl amine at
1608C for 24 h. Here, endo attack of benzylamine yields the in-
termediate endo amine–exo tosylate, which, owing to steric
The first step in the reaction sequence, the tosylation of iso-
hexides (isoidide 1a, isosorbide 1b, and isomannide 1c) was
performed according to our literature procedure,[10] and gave
the purified products in high yield (>90%) and high purity
(99% based on NMR and GC analyses).
It is known that the substitution of isohexide-based tosylates
can be effectively performed with high boiling monoalkyl
Scheme 1. Synthesis of dideoxy isohexide diamines.
1824
www.chemsuschem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2011, 4, 1823 – 1829

Renewable Rigid Diamines
Figure 2. Displacement ellipsoid plot of 3c in the crystal (50% probability
level). Only one of two independent molecules is shown. The absolute struc-
ture could not be determined from the X-ray data.
1), whereas the corresponding C22–N12–C72–C82 is
165.96(14)8 (molecule 2). The tricyclic benzyl protected amine
3c was deprotected similarly to 3a to afford the tricyclic
amine 4c, which was further purified by column chromatogra-
phy (methanol/chloroform 1:9) to give a colorless crystalline
solid of 85% yield in high purity (99% based on NMR and GC
analyses).
NMR analysis of 3c (Figure 1a) and 4c (Figure 1b) gave intri-
guing results. The simplicity of the 13C NMR spectra (see Sup-
porting Information), showing only three carbon signals for
the isohexide skeleton, suggests C2 symmetry, which is in ac-
cordance with the single crystal X-ray analysis. Surprisingly, the
1H NMR spectra of 3c and 4c show no coupling between the
proton at C2/C5 with either the bridge protons at C3/C4 or the
AB-system of the protons at C1/C6. The absence of coupling
between the proton at C2/C5 with the bridge protons at C3/
C4 is usually only observed for the isoidide configuration.
The H3–C3–C2–H2 (see structure of tricyclic compound
below) dihedral angle of approximately À578, obtained from
the X-ray data, should result in a
Figure 1. a) 1H NMR spectrum of 2,5-(benzylamino)-2,5-dideoxy-1,4:3,6-dia-
nhydro-d-mannitol, 3c. b) 1H NMR spectrum of 2,5-(amino)-2,5-dideoxy-
1,4:3,6-dianhydromannitol, 4c.
and electronic factors (secondary amine) is prone to undergo
an intramolecular SN2 reaction, in a similar fashion as proposed
by Bashford and Wiggins in the case of isoidide bistosylate
and methanolic ammonia.[6b] Whereas these authors reported
an isolated yield of the free amine (2,5-imino-1,4:3,6-dianhy-
dro-2,5-dideoxy-d-mannitol, 4c) of only 18%, we obtained an
isolated yield of 85% of 3c after purification by column chro-
matography [ethyl acetate/petroleum ether (1:9)]. This under-
lines the unprecedented efficiency of the benzylamine substi-
tution.
Compound 3c was identified by using 1H (Figure 1a) and
13C NMR spectroscopy (see Supporting Information) and ESI-
MS. Confirmation of the configuration deduced from NMR data
was obtained from single crystal X-ray diffraction studies on 3c
(Figure 2). Compound 3c crystallizes in the non-centrosymmet-
ric space group P21 with two independent molecules in the
asymmetric unit. The tricyclic core in the two molecules is
identical and the molecules have the same configuration. The
major difference is in the conformation of the benzyl substitu-
ent torsion angle; C21–N11–C71–C81 is 69.65(16)8 (molecule
coupling constant of 3.2 Hz,[14]
which means that H3 should
appear as a doublet. In a similar
manner the dihedral angles H1a–
C1–C2–H2 and H1b–C1–C2–H2
should give rise to 3J coupling
constants of 1.5 and 2.3 Hz, re-
spectively. Though small, these coupling constants should
1
result in multiplicity of the corresponding H signals. Since X-
ray data were only available for 3c, density functional theory
(DFT) calculations were used to verify the dihedral angles for
1
4c, as this compound gave a comparable H NMR spectrum.
A comparison of the calculated structural data for 3c with
the X-ray data shows that the DFT data are in good agree-
ment. Hence it is reasonable to assume that the calculated
data for 4c (Table 1) are correct. The presence of the benzyl
substituent appears to have no significant influence on the
highly rigid tricyclic skeleton, which is reflected in the similarity
ChemSusChem 2011, 4, 1823 – 1829
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
1825

D. S. van Es et al.
FDA.mth), hold 2 min at 708C,
ramp 108CminÀ1, final temperature
3008C, hold 2 min; total run time
27 min; detector, FID at 3008C.
GC–MS analysis was performed on
a Finnigan Mat GC8000 Top GC
Table 1. Selected dihedral angles, bond distances and angles calculated for 3c and 4c from DFT calculations
and single crystal X-ray diffraction (in parentheses).
Atoms
Dihedral angle [8]
3c 4c
Atoms
Bond distance [ꢂ]
Atoms
Bond Angles [8]
3c
3c
4c
4c
H3C3C4H4
H3C3C2H2
H1aC1C2H2
H1bC1C2H2
C2C3C4C5
50.4(49.7)
50.2
57.9
À74.5
52.7
C3C4
C3O1
C2N
1.544(1.528)
1.454(1.425)
1.503(1.489)
1.559(1.553)
1.543
1.462
1.504
1.559
O1C4C3
CNC
106.2(107.1)
104.0(103.2)
106.2
104.1
(carrier gas, He; flow, 1 mLminÀ1
split flow, 25 mLminÀ1; Chrompack
CP-Sil 5CB column, 30 mꢁ
;
57.5(À56.7)
À71.7(À70)
54.2(53)
C2C3
0.25 mmꢁ1.0 mm; GC program,
hold 2 min at 408C, ramp
66.6(66.5)
66.2
108CminÀ1
,
final
temperature
3008C) connected to a Finnigan
1
of the H NMR spectra of 3c and 4c. Recently, NMR data were
reported for the ether analogue of 4c, (3S,3aR,6aR)-hexahydro-
3,6-epoxyfuro[3,2-b]furan, which gave a comparable 1H NMR
spectrum.[15] Although highly intriguing from a theoretical
point of view, a full explanation of these effects falls beyond
the scope of our present study.
Mat Automass II quadrupole mass selective detector (EI, mass
range 40–400 Dalton, 150 ms sample speed). ESI mass spectrome-
try was carried out using a Bruker microTOF-Q instrument in posi-
tive ion mode (capillary potential of 4500 V). Melting points were
measured on a Thermal Fisher Scientific IA 9000 Series digital melt-
ing point apparatus. Differential scanning calorimetry (DSC) meas-
urements were conducted on a Perkin–Elmer Diamond series DSC.
The temperature range used was 20–2008C at a heating rate of
108CminÀ1. All hydrogenation experiments were performed in a
600 mL Parr series 5000 Mini Bench-top reactor made from Alloy
C-276, equipped with mechanical magnetic drive stirrer. Short path
distillations were carried out using a Buchi Glass Oven B-585 (Ku-
gelrohr).
Conclusions
We have shown that our new three-step strategy for the syn-
thesis of dideoxy-diamino isohexides is highly effective for the
stereocontrolled synthesis of high purity dideoxy-diamino isoi-
dide 4a and dideoxy-diamino isosorbide 4b. Preliminary re-
sults on the scale-up of these reactions to kilogram scale are
encouraging and will be the subject of future publications.
Whereas it is not possible to obtain the dideoxy-diamino iso-
mannide isomer with the current strategy, we have shown that
the intriguing tricyclic amine 4c can be prepared with both
high yield and purity. Investigations into the potential applica-
tions of this rigid tricyclic amine are currently in progress.
X-ray crystal structure determination of 3c
C13H15NO2, Molecular weight=217.26, colorless block, 0.30ꢁ0.24ꢁ
0.09 mm3, monoclinic, P21 (no. 4), a=12.7633(5), b=5.6470(2), c=
15.1449(5) ꢂ, b=95.3791(9)8, V=1086.75(7) ꢂ3, Z=4, Dx =
1.328 gcmÀ3, m=0.09 mmÀ1. 15924 reflections were measured on a
Bruker Kappa ApexII diffractometer with sealed tube and Triumph
monochromator (l=0.71073 ꢂ) up to a resolution of (sin q/l)max
=
0.65 ꢂÀ1 at a temperature of 150(2) K. Intensity data were integrat-
ed with the Saint software.[16] Absorption correction and scaling
was performed based on multiple measured reflections with
SADABS[17] (0.83–0.86 correction range). As the absolute structure
could not be determined reliably, Friedel pairs were merged. 2758
reflections were unique (Rint =0.016), of which 2635 were observed
(I>2sI). The structure was solved with Direct Methods using the
program SHELXS-86 and refined with SHELXL-97 against F2 of all
reflections.[18] Non-hydrogen atoms were refined with anisotropic
displacement parameters. Hydrogen atoms were located in differ-
ence-Fourier maps and refined freely with isotropic displacement
parameters. 409 parameters were refined with one restraint. R1/
wR2 =0.0299/0.0795 (I>2s), R1/wR2 =0.0318/0.0814 (all reflections),
S=1.047. Residual electron density between À0.21 and 0.22 eꢂ3.
Geometry calculations and checking for higher symmetry was per-
formed with the PLATON program.[19] The Cambridge Crystallo-
graphic Data Centre 836435 contains the supplementary crystallo-
graphic data for this paper.[20] DFT calculations were performed
using the GAMESS interface on ChemBio3D Ultra, using the B3LYP
method and a TZV basis set.
Experimental Section
1,4:3,6-dianhydro-2,5-di-O-p-tosyl-d-mannitol (2c) was synthesized
according to the literature.[10] Isomannide (Sigma–Aldrich), isosor-
bide and isoidide (ex-Roquette), p-toluenesulphonyl chloride
(Fluka, 99%), pyridine (Merck, p. a.), benzyl amine (Sigma–Aldrich,
99.5%), diethyl ether (Merck, p. a.), petroleum ether (Acros Organ-
ics, 40–608C), ethyl acetate (Acros Organics, +99%), silica gel (Alfa
Aesar, 230–400 mesh), Pearlman’s catalyst, Pd(OH)2/C (20% Pd on
activated carbon, unreduced, 55.02% water wet paste, BASF Escat
1951; Strem), hydrogen (ꢀ99.9% purity, Linde), activated carbon
(Norit, CN1), magnesium sulfate (Acros Organics, 99% extra pure,
dried, contains 3–4 moles of water), Celite 545 coarse (Fluka),
chloroform-D (99.8 atom% D, Sigma–Aldrich), D2O (>99.8%,
Merck). All the chemicals were used as received, unless stated oth-
erwise.
FTIR spectra were obtained on a Varian Scimitar 1000 FTIR spec-
trometer equipped with a Pike MIRacle ATR Diamond/ZnSe single
reflection plate and a DTSG detector. The measurement resolution
was set at 4 cmÀ1, and the spectra were collected in the range
4000–650 cmÀ1 with 32 co-added scans. NMR spectra were record-
ed on a Bruker Avance III spectrometer operating at 400.17 MHz
(1H) and 100.62 MHz (13C). Gas chromatography was performed on
an Interscience Focus GC equipped with an AS 3000 series auto
sampler: injection volume, 1 mL; injector temperature, 2758C; split
ratio, 1:33; column flow (at 2758C), 50 mLminÀ1 He; GC column,
Restek Rxi-5 ms, 30 mꢁ0.25 mmꢁ0.25 mm; GC program (2,5-
Synthesis of 1,4:3,6-dianhydro-2,5-di-O-p-tosyl-d-iditol 2a
A 2-necked round-bottom flask was charged with a solution of isoi-
dide 1a (50.0 g, 0.34 mol) in pyridine (150 mL) under nitrogen at-
mosphere. The mixture was cooled to 0–58C. A solution of p-tolu-
ene sulfonyl chloride (130.5 g, 0.68 mol) in pyridine (350 mL) was
added drop wise over 30 min. After 3 h, the reaction mixture was
1826
www.chemsuschem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2011, 4, 1823 – 1829

Renewable Rigid Diamines
placed in a refrigerator overnight. The mixture was then poured
onto ice-water (2.5 L) and stirred for 1 h. The sandy solid, obtained
following filtration, was subsequently ground and washed thor-
oughly with water, dilute HCl (0.2M), and finally water, followed by
suction filtration. The crude product was recrystallized from etha-
nol yielding 2a as colorless needles. Yield: 139.5 g, 90%; m.p. 104–
1058C (lit.[9] m.p. 105.58C); 1H NMR (400 MHz, CDCl3): d=7.77 (d,
J=8.4 Hz, 4H), 7.36 (d, J=8 Hz, 4H), 4.86 (d, J=3 Hz, 2H), 4.58 (s,
2H), 3.94 (dd, J=11.3, 1 Hz, 2H), 3.77 (dd, J=11.1, 3.6 Hz, 2H),
2.45 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=145.4, 133.0, 130.0,
127.7, 85.0, 82.4, 72.2, 21.6 ppm; IR (neat): n˜ =1597, 1359, 1297,
Synthesis of 2,5-bis(benzylamino)-2,5-dideoxy-1,4:3,6-dia-
nhydro-d-sorbitol 3b
A 100 mL three-necked round-bottom flask, equipped with a mag-
netic stirrer, and a reflux condenser with a nitrogen inlet, was
charged with isosorbide bistosylate 2b (5 g, 0.011 mol), and freshly
distilled benzyl amine (35 mL). The reaction mixture was stirred at
1608C under a nitrogen atmosphere for 24 h. After completion of
the reaction, the yellow reaction mixture was cooled to room tem-
perature and diethyl ether was added (100 mL) with vigorous stir-
ring. The precipitated colorless crystalline benzylammonium tosy-
late salt was filtered off, and this procedure was repeated until no
further precipitation was observed. Subsequently, the excess dieth-
yl ether and benzyl amine were carefully distilled off under re-
duced pressure using a high vacuum pump (1ꢁ10À1 mbar) at 50–
608C (oil bath temperature) for 3 h. The crude product (pale
yellow viscous oil) was used in the subsequent step for the hydro-
genolysis reaction. For analytical purposes part of the crude prod-
uct was purified by short path distillation using a Kugelrohr oven
at 2008C at 50 mbar for 1 h. The pure isosorbide bisbenzyl amine
3b was obtained as a colorless viscous oil. Yield: 2.5 g, 70%;
1H NMR (400 MHz, CDCl3): d=7.36–7.22 (m, 10H), 4.58 (t, J=4ꢁ
2 Hz, 1H), 4.47 ppm (d, J=4 Hz, 1H), 4.0–3.96 (m, 1H), 3.94–3.90
(m, 2H), 3.81–3.73 (m, 4H), 3.35–3.28 (m, 3H), 1.64 (bs, 2H, 2xNH
ppm; 13C NMR (100 MHz, CDCl3): d=140.0, 139.6, 128.3, 128.0,
126.9, 88.0, 79.8, 73.7, 71.2, 65.4, 61.7, 52.3, 52.1 ppm; IR (neat): n˜ =
1176, 1079, 1040, 966 cmÀ1
.
Synthesis of 1,4:3,6-dianhydro-2,5-di-O-p-tosyl-d-sorbiol 2b
A 2-necked round-bottom flask was charged with a solution of iso-
sorbide 1b (50.0 g, 0.34 mol) in pyridine (150 mL) under a nitrogen
atmosphere. The mixture was cooled to 0–58C. A solution of p-tol-
uene sulfonyl chloride (130.5 g, 0.68 mol) in pyridine (350 mL) was
added drop wise over 30 min. After 3 h, the reaction mixture was
placed in a refrigerator overnight. Then, the mixture was poured
onto ice-water (2.5 L) and stirred for 1 h. The sandy solid, obtained
following filtration, was subsequently ground and washed thor-
oughly with water, dilute HCl (0.2m), and finally water followed by
suction filtration. The crude product was recrystallized from etha-
nol yielding 2b as colorless needles. Yield: 145 g, 93%; m.p. 106.5–
108.58C (lit.[8a] m.p. 101–1028C); 1H NMR (400 MHz, CDCl3): d=
7.80–7.75 (m, 4H), 7.36–7.32 (m, 4H), 4.87–4.82 (m, 2H), 4.59 (t, J=
4.8 Hz, 1H), 4.48 (d, J=4.5 Hz, 1H), 3.92 (d, J=11.3 Hz, 1H), 3.88–
3.82 (m, 2H), 3.66 (dd, J=9.8, 6.4 Hz, 1H), 2.45 ppm (s, 6H);
13C NMR (100 MHz, CDCl3): d=145.3, 145.2, 132.9, 129.8, 127.7,
85.5, 83.2, 80.2, 78.2, 73.1, 69.7, 21.5 ppm; IR (neat): n˜ =1596, 1366,
3310, 2936, 2859, 1642, 1498, 1453, 1358, 1199, 1079, 1028 cmÀ1
ESI-HRMS: MH+, C20H25N2O2 calcd. 325.1916, found 325.1897.
;
Synthesis of 2,5-(benzylamino)-2,5-dideoxy-1,4:3,6-dianhy-
dro-d-mannitol 3c
1176, 1087, 1049, 967 cmÀ1
.
A 100 mL three-necked round-bottom flask, equipped with a mag-
netic stirrer, and a reflux condenser with a nitrogen inlet, was
charged with isoidide bistosylate 2a (5 g, 0.011 mol), and freshly
distilled benzyl amine (35 mL). The reaction mixture was stirred at
1608C under a nitrogen atmosphere for 24 h. After completion of
the reaction, the yellow reaction mixture was cooled to room tem-
perature and diethyl ether was added (100 mL) with vigorous stir-
ring. The precipitated white crystalline benzylammonium tosylate
salt was then filtered off, and this procedure was repeated until no
further precipitation was observed. Subsequently, the excess dieth-
yl ether and benzyl amine were carefully distilled off under re-
duced pressure using a high vacuum pump (1ꢁ10À1 mbar) at 50–
608C (oil bath temperature) for 3 h. The crude product (pale
yellow viscous oil) was used in the subsequent step for the hydro-
genolysis reaction. For analytical purposes part of the crude prod-
uct was purified by column chromatography over silica gel and 1:9
ethyl acetate/petroleum ether as eluent. The pure tricyclic benzyl
amine 3c was obtained as a colorless crystalline solid. Recrystalliza-
tion from ethyl acetate afforded needle shaped crystals. Yield:
1.8 g, 75%; m.p. 49–518C; 1H NMR (400 MHz, CDCl3): d=7.49 (d,
J=7.3 Hz, 2H), 7.35 (t, J=7.5 Hz, 2H), 7.29–7.26 (m, 1H), 4.58 (s,
2H), 4.12 (d, J=8.5 Hz, 2H), 4.08–4.00 (m, 2H), 3.79 (d, J=7.3 Hz,
2H), 3.38 ppm (s, 2H); 13C NMR (100 MHz, CDCl3): d=139.5, 128.4,
128.2, 126.9, 78.9, 71.3, 64.9, 53.7 ppm; IR (neat): n˜ =2987, 2872,
Synthesis of 2,5-bis(benzylamino)-2,5-dideoxy-1,4:3,6-dia-
nhydro-d-iditol 3a
A 100 mL three-necked round-bottom flask, equipped with a mag-
netic stirrer, and a reflux condenser with a nitrogen inlet, was
charged with isomannide bistosylate 2c (5.0 g, 0.011 mol), and
freshly distilled benzyl amine (35 mL). The reaction mixture was
stirred at 1608C under nitrogen atmosphere for 24 h. After comple-
tion of the reaction, the yellow reaction mixture was cooled to
room temperature and diethyl ether was added (100 mL) with vig-
orous stirring. The precipitated crystalline benzylammonium tosy-
late salt was filtered, and this procedure was repeated until no fur-
ther precipitation was observed. Subsequently, the excess diethyl
ether and benzyl amine were carefully distilled off under reduced
pressure using a high vacuum pump (1ꢁ10À1 mbar) at 50–608C
(oil bath temperature) for 3 h. The crude product (pale yellow vis-
cous oil, 3.0 g) was used in the subsequent step for the hydroge-
nolysis reaction. For analytical purposes part of the crude product
was purified by short path distillation using a Kugelrohr oven at
2258C at 50 mbar for 1 h. The pure isoidide bisbenzyl amine 3a
was obtained as a hygroscopic fluffy white solid. Yield: 2.8 g, 79%;
m.p. 48–508C (lit.[12] m.p. 508C); 1H NMR (400 MHz, CDCl3): d=
7.34–7.22 (m, 10H), 4.53 (s, 2H), 3.91 (dd, J=9.3, 5 Hz, 2H), 3.86–
3.78 (m, 4H), 3.67 (dd, J=9.3, 3 Hz, 2H), 3.33 (dd, J=4.8, 3.3 Hz,
2H), 1.48 ppm (bs, 2H, 2xNH); 13C NMR (100 MHz, CDCl3): d=139.7,
128.5, 128.1, 127.1, 87.2, 72.8, 64.1, 52.0 ppm; IR (neat): n˜ =3254,
2896, 1626, 1490, 1453, 1358, 1200, 1063, 1028 cmÀ1; ESI-HRMS:
MH+, C20H25N2O2 calcd. 325.1916, found 325.1894.
1635, 1494, 1454, 1363, 1320, 1207, 1165, 1116, 1063, 985 cmÀ1
ESI-HRMS: MH+, C13H16NO2 calcd. 218.1181, found 218.1174.
;
ChemSusChem 2011, 4, 1823 – 1829
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
1827

D. S. van Es et al.
300 rpm, the reactor was heated to 508C, and stirring was contin-
ued for 20 h. Reaction progress was monitored by GLC analysis of
samples taken at intervals by using the dip-tube. Once complete
conversion of the starting material had been achieved the reactor
was cooled to room temperature, excess hydrogen pressure was
vented off and the reactor was flushed with nitrogen (4 bar) 3
times. The black suspension was then filtered over a G-3 glass filter
containing Celite, giving a pale yellow clear solution, which was
evaporated to dryness under reduced pressure using a rotary evap-
orator yielding 4c (0.6 g). Further purification of the crude product
using column chromatography on silica gel and 1:9 methanol/
chloroform as eluent yielded 4c as an off-white crystalline solid
with >95% purity (from NMR and GC analysis). Yield: 0.55 g, 75%;
Synthesis of 2,5-diamino-2,5-dideoxy-1,4:3,6-dianhydroiditol
4a
A pressure reactor was charged with the catalyst (Pd(OH)2/C)
(0.5 g, 0.47 mmol), crude 2,5-bis(benzylamino)-1,4:3,6-dianhydro-
2,5-dideoxy-d-iditol 3a (2.5 g, 7.7 mmol) and degassed ethanol
(75 mL). Next, the reactor was purged with nitrogen (4 bar) 3
times, and then pressurized with hydrogen to 10 bar. Under stirring
at 300 rpm, the reactor was heated to 508C, and stirring was con-
tinued for 20 h. Reaction progress was monitored by GLC analysis
of samples taken at intervals by using the dip-tube. Once complete
conversion of the starting material had been achieved the reactor
was cooled to room temperature, excess hydrogen pressure was
vented off and the reactor was flushed with nitrogen (4 bar) 3
times. The black suspension was filtered over a G-3 glass filter con-
taining Celite, giving a pale yellow clear solution, which was
evaporated to dryness under reduced pressure using a rotary evap-
orator yielding 4a (1.0 g). The crude product was further purified
by recrystallization from ethanol/methanol mixture (2:0.5) and af-
forded 4a as colorless crystalline solid (0.95 g, 86%) with >98%
purity (from NMR, GC analysis). Yield: 0.95 g, 86%; m.p. 60–628C
(lit.[10] m.p. 60–628C); 1H NMR (400 MHz, D2O): d=4.49 (bs, 2H),
3.87–3.84 (m, 2H), 3.64 (d, J=9.3 Hz, 2H), 3.44 ppm (bs, 2H);
13C NMR (100 MHz, D2O): d=88.3, 74.4, 57.3 ppm; IR (neat): n˜ =
3351, 2825, 1597, 1537, 1200, 1080, 1035 cmÀ1; ESI-HRMS: MH+,
C6H13N2O2 calcd. 145.0977, found 145.0972.
1
m.p. 95–978C (lit.[13] m.p. 99–1008C); H NMR (400 MHz, CDCl3): d=
4.38 (s, 2H), 3.81 (d, J=8.1 Hz, 2H), 3.69 (d, J=8.1 Hz, 2H), 3.48 (s,
2H), 1.58 ppm(s, 1H, 1xNH); 13C NMR (100 MHz, CDCl3): d=77.6,
74.6, 61.5 ppm; IR (neat): n˜ =3163, 2972, 2860, 1473, 1443, 1298,
1223, 1165, 1060; ESI-HRMS: MH+, C6H10NO2 calcd. 128.0712, found
128.0696.
Acknowledgements
Dr. G. Frissen and W. Teunissen are gratefully acknowledged for
NMR and GC–MS analyses. Roquette Freres and Norit are ac-
knowledged for supplying isoidide and activated carbon, respec-
tively. This work is part of the research programme of the Dutch
Polymer Institute (project number653.
Synthesis of 2,5-diamino-2,5-dideoxy-1,4:3,6-dianhydrosor-
bitol 4b
Keywords: amines
resources · isomers
·
chirality
·
polycycles
·
renewable
A pressure reactor was charged with the catalyst (Pd(OH)2/C)
(0.5 g, 0.47 mmol), crude 2,5-bis(benzylamino)-1,4:3,6-dianhydro-
2,5-dideoxy-d-sorbitol 3b (2.5 g, 7.7 mmol) and degassed ethanol
(75 mL). The reactor was purged with nitrogen (4 bar) 3 times, and
then pressurized with hydrogen to 10 bar. Under stirring at
300 rpm, the reactor was heated to 508C, and stirring was contin-
ued for 20 h. Reaction progress was monitored by GLC analysis of
samples taken at intervals by using the dip-tube. Once complete
conversion of the starting material had been achieved the reactor
was cooled to room temperature, excess hydrogen pressure was
vented off and the reactor was flushed with nitrogen (4 bar) 3
times. The black suspension was filtered over a G-3 glass filter con-
taining Celite, giving a pale yellow clear solution, which was
evaporated to dryness under reduced pressure using a rotary evap-
orator yielding 4b (0.9 g). The crude product was further purified
by recrystallization from ethanol/methanol mixture (2:0.5) and af-
forded 4b as colorless crystalline solid with >98% purity (from
NMR, GC analysis). Yield: 0.85 g, 77%; m.p. 54–568C (lit.[8a] b.p.
105–1108C); 1H NMR (400 MHz, D2O): d=4.90 (t, J=4.8 Hz, 1H),
4.80 (d, J=4.0 Hz, 1H), 4.15 (dt, J=9.9, 6.2 Hz, 2H), 4.07–3.91 (m,
3H), 3.77 ppm (dd, J=9.6, 7.6 Hz, 1H); 13C NMR (100 MHz, D2O):
d=85.8, 80.5, 71.7, 69.4, 56.3, 52.4 ppm; IR (neat): n˜ =3356, 2885,
1578, 1529, 1200, 1080, 1039 cmÀ1 ppm; ESI-HRMS: MH+,
C6H13N2O2 calcd. 145.0977, found 145.0966.
[1] a) G. O. Oleksandr, R. S. Dmytro, V. M. Dmitriy, T. A. Andrey, K. V. Komar-
ov, Chem. Rev. 2011, 111, 5506–5568; b) GB1012563, 1965; c) W. C. Tate,
G. J. Scruggs, US3223752, 1965; d) F. L. Charbonneau, E. R. Johnson,
B. H. Witteler, G. Khanarian, US5959066, 1999; e) F. L. Charbonneau, G.
Khanarian, E. R. Johnson, B. H. Witteler, A. J. Flint, US6063495, 2000;
f) F. L. Charbonneau, E. R. Johnson, US6063465, 2000; g) V. J. Kurian, Y.
Ling, US6737481, 2004; h) J. Thiem, H. Lꢃders, Starch/Staerke 1984, 36,
170–176; i) J. Thiem, H. Lꢃders, Polym. Bull. 1984, 11, 365–369.
[2] a) H. R. Kricheldorf, Z. Gomourachvili, Macromol. Chem. Phys. 1997, 198,
3149; b) D. J. Adelman, L. F. Charbonneau, S. Ung, U.S. Patent 6656577;
c) M. Okada, Y. Okada, K. Aoi, J. Polym. Sci., Part A Polym. Chem. 1995,
33, 2813; d) M. Okada, K. Tsunoda, K. Tachikawa, K. Aoi, J. Appl. Polym.
Sci. 2000, 77, 338.
[3] a) J. Wu, P. Eduard, S. Thiyagarajan, J. van Haveren, D. van Es, C. E.
Koning, M. Lutz, F. Cꢄlia Guerra, ChemSusChem 2011, 4, 599–603; b) F.
Fenouillot, A. Rousseau, G. Colomines, R. Saint-Loup, J. P. Pascault, Prog.
Polym. Sci. 2010, 35, 578–622.
[4] a) J. Thiem, Makromol. Chem. 1986, 187, 2775–2785; b) J. Thiem, F.
Bachmann, Makromol. Chem. 1991, 192, 2163–2182.
[5] a) L. Jasinska, M. Villani, J. Wu, D. van Es, E. Klop, S. Rastogi, C. E. Koning,
Macromolecules 2011, 44, 3458–3466; b) J. Pfeffer, M. Ortelt, E. Spyrou,
T. Hass, U. Korek, H. Schmidt, U. Dingerdissen (Evonik Degussa), WO
2011000585, 2011, [Chem. Abstr. 2011, 154, 89176]; c) J. Pfeffer, M.
Ortelt, E. Spyrou, T. Hass, U. Korek, H. Schmidt; U. Dingerdissen (Evonik
Degussa), WO 2011000586, 2011; [Chem. Abstr. 2011, 154, 110159]; d) E.
Spyrou, J. Pfeffer, H. Loesch, M. Ebbing-Ewald, H. Grosse-Beck (Evonik
Degussa), WO 2011000587, 2011 [Chem. Abstr. 2011, 154, 110160].
[6] a) R. Montgomery, L. F. Wiggins, J. Chem. Soc. 1946, 393–396; b) V. G.
Bashford, L. F. Wiggins, J. Chem. Soc. 1950, 371–374.
[7] A. C. Cope, T. Y. Shen, J. Am. Chem. Soc. 1956, 78, 3177–3182.
[8] a) J. Kuszmann, G. Medgyes, Carbohydr. Res. 1980, 85, 259–269; b) T. G.
Archibald, K. Baum, Synth. Commun. 1989, 19, 1493–1498.
[9] For safe handling of organic azides, (NC +NO)/NN >3, where NX =
number of X atoms in the azide; isohexide diazide formulae amount to
Synthesis of 2,5-(amino)-2,5-dideoxy-1,4:3,6-dianhydroman-
nitol 4c
A pressure reactor was charged with the catalyst (Pd(OH)2/C)
(0.125 g, 0.235 mmol), crude 2,5-(benzylamino)-1,4:3,6-dianhydro-
2,5-dideoxy-d-mannitol 3c (1.25 g, 5.75 mmol) and degassed etha-
nol (50 mL). The reactor was purged with nitrogen (4 bar) 3 times,
and then pressurized with hydrogen to 10 bar. Under stirring at
1828
www.chemsuschem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2011, 4, 1823 – 1829

Renewable Rigid Diamines
8/6=1.3 (!); see also H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew.
Chem. 2001, 113, 2056–2075; Angew. Chem. Int. Ed. 2001, 40, 2004–
2021.
[15] P. Tundo, F. Aricꢆ, G. Gauthier, A. Baldacci, C. R. Chimie 2011, 14, 652–
655.
[16] Bruker, SAINT-Plus, Bruker AXS Inc., Madison, Wisconsin, USA, 2001.
[17] G. M. Sheldrick, SADABS: Area-Detector Absorption Correction, v2.10,
1999, Universitꢅt Gçttingen, Germany.
[10] S. Thiyagarajan, L. Gootjes, W. Vogelzang, J. Wu, J. van Haveren, D.
van Es, Tetrahedron 2011, 67, 383–389.
[11] S. Imm, S. Bꢅhn, M. Zhang, L. Neubert, H. Neumann, F. Klasovsky, J. Pfeff-
er, T. Haas, M. Beller, Angew. Chem. 2011, 123, 7741–7745; Angew.
Chem. Int. Ed. 2011, 50, 7599–7603.
[12] T. Catherine, A-W. Sara, Y. Jeffrey, L. Hengyuan, K. Donald S, (Senomyx,
INC), WO 2011/002871, 2011.
[18] G. M. Sheldrick, Acta Crystallogr. Sec. A 2008, 64, 112–122.
[19] A. L. Spek, Acta Crystallogr. Sec. D 2009, 65, 148–155.
[20] These data can be obtained free of charge from http://www.ccdc.
cam.ac.uk/cgi-bin/catreq.cgi.
[13] S. Kumar, U. Ramachandran, Tetrahedron 2005, 61, 4141–4148.
[14] C. A. G. Haasnoot, F. A. A. M. DeLeeuw, C. Altona, Tetrahedron 1980, 36,
2783–2792.
Received: July 25, 2011
Published online on November 25, 2011
ChemSusChem 2011, 4, 1823 – 1829
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
1829