Synthesis of trisubstituted ureas by a multistep sequence utilizing recyclable magnetic reagents and scavengers

Article abstract of DOI:10.1002/chem.201300358

Unprecedented magnetic borohydride exchange (mBER), magnetic Wang aldehyde (mWang) and magnetic amine resins were prepared from highly magnetic polymer-coated cobalt or iron nanoparticles. Microwave irradiation was used to obtain excellent degrees of functionalization (>95 %) and loadings (up to 3.0 mmol g^-1) in short reaction times of 15 min or less. A small library of ureas and thioureas was synthesized by the exclusive application of these magnetic resins. As a first step, a reductive amination of aromatic and aliphatic aldehydes was carried out with mBER. The excess of primary amine needed to complete the reaction was subsequently scavenged selectively by mWang. Simple magnetic decantation from the resins resulted in secondary amines in good to excellent yields and purities. The used magnetic resins were efficiently regenerated and reused for the next run. In a second step, the secondary amines were converted to trisubstituted (thio)ureas in excellent yields and purities by stirring with an excess of iso(thio)cyanate, which was scavenged by addition of the magnetic amine resin after completion of the reaction. The whole reaction sequence is carried out without any purification apart from magnetic decantation; moreover, conventional magnetic stirring can be used as opposed to the vortexing required for polystyrene resins. Do it magnetically! A small library of trisubstituted ureas and thioureas was synthesized in high yields and purities by a multistep sequence exclusively applying magnetic reagents and scavengers. No purification steps were necessary apart from magnetic decantation, and the resins were recycled if possible. The novel resins were conveniently and efficiently prepared starting from polymer-coated magnetic Co/C or Fe/C nanobeads by microwave protocols. Copyright

Full text of DOI:10.1002/chem.201300358

FULL PAPER
Synthetic Methods
Q. M. Kainz, M. Zeltner, M. Rossier,
W. J. Stark, O. Reiser* ....... &&&& — &&&&
Synthesis of Trisubstituted Ureas by a
Multistep Sequence Utilizing Recy-
clable Magnetic Reagents and Scav-
engers
Do it magnetically! A small library of
trisubstituted ureas and thioureas was
synthesized in high yields and purities
by a multistep sequence exclusively
applying magnetic reagents and scav-
engers. No purification steps were nec-
essary apart from magnetic decanta-
tion, and the resins were recycled if
possible. The novel resins were con-
veniently and efficiently prepared
starting from polymer-coated magnetic
Co/C or Fe/C nanobeads by microwave
protocols.
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DOI: 10.1002/chem.201300358
Synthesis of Trisubstituted Ureas by a Multistep Sequence Utilizing
Recyclable Magnetic Reagents and Scavengers
Quirin M. Kainz,[a] Martin Zeltner,[b] Michael Rossier,[b] Wendelin J. Stark,[b] and
Oliver Reiser*[a]
Abstract: Unprecedented magnetic
borohydride exchange (mBER), mag-
netic Wang aldehyde (mWang) and
magnetic amine resins were prepared
from highly magnetic polymer-coated
cobalt or iron nanoparticles. Micro-
wave irradiation was used to obtain
excellent degrees of functionalization
(>95%) and loadings (up to
3.0 mmolgÀ1) in short reaction times of
15 min or less. A small library of ureas
and thioureas was synthesized by the
exclusive application of these magnetic
resins. As a first step, a reductive ami-
nation of aromatic and aliphatic alde-
hydes was carried out with mBER. The
excess of primary amine needed to
complete the reaction was subsequent-
ly scavenged selectively by mWang.
Simple magnetic decantation from the
resins resulted in secondary amines in
good to excellent yields and purities.
The used magnetic resins were effi-
ciently regenerated and reused for the
next run. In a second step, the second-
AHCTUNGTRENNaGUN ry amines were converted to trisubsti-
tuted (thio)ureas in excellent yields
and purities by stirring with an excess
ACHTUNGTRENNUNG
of isoACTHNUGRTNEUNG(thio)cyanate, which was scav-
enged by addition of the magnetic
amine resin after completion of the re-
action. The whole reaction sequence is
carried out without any purification
apart from magnetic decantation;
moreover, conventional magnetic stir-
ring can be used as opposed to the vor-
texing required for polystyrene resins.
Keywords: amination
·
magnetic
reagents · microwave chemistry ·
nanoparticles · synthetic methods
Introduction
regeneration of the reagents supported on the polymer
resins.[4] Workup consists of simple filtration and evapora-
tion of the solvents, leads generally to very clean products in
high yield and avoids complex and expensive purification
steps that also might generate additional waste.
Initiated by the pioneering work of Merrifield[1] five decades
ago, polymer resins as insoluble supports have been of con-
siderable and steadily growing interest in the field of organic
synthesis. Solid-phase organic synthesis (SPOS)[2] revolution-
ized the synthesis of polypeptides and polynucleotides by
the adaptation of established solution-phase reactions to the
solid phase. Driven by the demand of the pharmaceutical in-
dustry for high-speed parallel synthesis, an alternative solu-
tion-phase technique utilizing reagents,[3,4] catalysts[5] and
scavengers[6] supported on functional polymers evolved re-
cently. In contrast to SPOS, this complementary approach is
considerably simpler, since it dispenses with the need for
linker chemistry and spares two additional steps for attach-
ing the starting material to the resin and cleaving the prod-
uct from the solid support.[7]Additional advantages are the
facile monitoring of reaction progress by standard analytical
techniques like TLC and potential reuse of the catalysts and
While a lot of effort was put into the diversification of re-
agents, catalysts and scavengers, the resins themselves are
still dominated largely by simple cross-linked polystyrene.
To bring the supports to the next level, we envisaged intro-
ducing highly magnetic cores into the polystyrene beads to
enable even quicker and more convenient separation of the
supports from reaction mixtures by rapid magnetic decanta-
tion. This would avoid clogging of filters, facilitate recovery
and subsequent recycling of the resins and allow for continu-
ous-flow applications using magnetic fields rather than
membranes to contain the supports.[8] Recently, Stark et al.
developed the large-scale synthesis (>30 ghÀ1) of carbon-
coated cobalt (Co/C)[9] and iron (Fe/C)[10] nanobeads by re-
ducing flame-spray pyrolysis of inexpensive metal carboxy-
lates. The raw materials cost for manufacturing carbon-
coated nanoparticles by this route can be estimated as less
than 100 USDkgÀ1.[11] These nanoparticles have excellent
thermal and chemical stability due to the graphene-like
shell, and the core of pure metal leads to an exceptionally
high saturation magnetization of up to 158 emugÀ1, which is
five times higher than for common iron oxide (e.g., magnet-
ite) beads.[12] Effective covalent and/or non-covalent func-
tionalization of the surface[13] led to applications in the ex-
traction of organic compounds and metals from aqueous sol-
utions up to the ton-per-hour scale,[14] in the purification of
[a] Q. M. Kainz, Prof. Dr. O. Reiser
Institute for Organic Chemistry, University of Regensburg
Universitꢁtsstrasse 31, 93053 Regensburg (Germany)
Fax : (+49)941-9434121
E-mail: Oliver.Reiser@chemie.uni-regensburg.de
[b] M. Zeltner, Dr. M. Rossier, Prof. Dr. W. J. Stark
Institute for Chemical and Bioengineering
Department of Chemistry and Applied Biosciences, ETH Zurich
Wolfang-Pauli-Strasse 10, 8093 Zurich(Switzerland)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300358.
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Synthesis of Trisubstituted Ureas
FULL PAPER
blood[15] and as recyclable sup-
ports for catalysts.[16,8] To in-
crease the loading with func-
tional groups by at least one
order of magnitude, polymer
shells were introduced by sur-
face-initiated ring-opening me-
A
E
polymerization
(ROMP)[17] or radical polymeri-
zation on the nanoparticle sur-
face.[18,19] ROMP-based scav-
engers for Mitsunobu reactions
as well as recyclable acylation
reagents were already establish-
ed.[20]
Figure 1. Magnetic recovery of polystyrene-coated nanobeads 1 from a CH2Cl2 solution. The golden-coloured
cylinder is a neodymium-based magnet.
and the exceptionally high magnetic moment of the metal
core leads to an overall saturation magnetization
Building on the results of Kaldor et al.[21] and Guinꢂ
et al.,[22] we herein report the—to the best of our knowl-
edge—first multistep synthesis achieved by exclusively com-
bining magnetic reagents and scavengers. A small library of
secondary amines was prepared by reductive amination fol-
lowed by conversion to trisubstituted ureas or thioureas. All
magnetic resins were functionalized by quick and efficient
microwave protocols and recycled for several runs whenever
possible.
(>33 emugÀ1)[19] that allows rapid separation of the hybrid
material from reaction mixtures (Figure 1). Neither irrever-
sible aggregation of the nanobeads nor limited recovery was
observed under the conditions used in this work. Besides
magnetic separation, the nanoparticles can be agitated by in-
ternal or external magnetic stirring, and this is a distinct ad-
vantage over polystyrene resins, which require agitation by
vortexing.
Preparation of mBER (4) via resin-bound benzylamine 2
was envisioned by quaternization with methyl iodine and
counterion exchange with an aqueous solution of sodium
borohydride (Scheme 1). Thus, a protocol for the Gabriel
synthesis described by Rotello et al.[24] was modified to use a
focussed microwave oven to quickly and efficiently heat the
metal nanoparticles, which are highly susceptible to micro-
wave irradiation,[25] and this allowed the reaction time for
the functionalization to be shortened to 5 min. After cleav-
age with hydrazine the amino-modified beads 2 were ob-
tained with a loading of 3 mmolgÀ1 (95% of benzyl chloride
substituted), as determined by elemental microanalysis. The
reaction was conveniently monitored by using attenuated
total reflectance IR spectroscopy (ATR-IR).[26] The func-
tionalized nanobeads 2 can be applied as scavengers for
electrophiles (see below). However, the planned quaterniza-
tion with methyl iodide en route to 4 was not exhaustive ac-
cording to elemental analysis and it was impossible to moni-
tor the reaction progress conclusively by ATR-IR.
Results and Discussion
Synthesis of magnetic borohydride resin (mBER): To syn-
thesize a magnetic variant of the borohydride exchange
resin (BER)[23] carbon-coated cobalt or iron nanoparticles
with an additional polystyrene shell (1) were used as basis
(Scheme 1). They were easily prepared on multigram scale
in three steps starting from pristine Co/C or Fe/C nano-
beads.[19] High loadings of 3.0–3.5 mmol benzyl chloride moi-
eties per gram of magnetic resin were obtained for 1, as de-
termined by chlorine microanalysis. The swelling of the
resin is analogous to that of conventional polystyrene beads,
Therefore, an alternative synthetic route was developed.
Direct conversion of benzyl chloride moieties to quaternary
ammonium cations has been reported for the synthesis of
water-soluble calix[n]arene[27] or porphyrins[28] by using tri-
methylamine gas or, more conveniently, aqueous or ethanol-
ic solutions of trimethylamine with the addition of co-sol-
vents. The latter method was applied to benzyl chloride
functionalized nanobeads 1 by using a 33% ethanolic solu-
tion of trimethylamine and DMF as co-solvent ensuring effi-
cient swelling of the polystyrene shell to prepare nanobeads
loaded with quaternary ammonium cations (3, Scheme 1).
Stirring for two days at room temperature as indicated in
the literature[27,28] led to a good degree of substitution
(91%), as concluded from nitrogen elemental analysis
(Table 1, entry 1). Again, microwave irradiation was used to
Scheme 1. Microwave-assisted synthesis of magnetic borohydride ex-
change resin 4 (mBER).
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O. Reiser et al.
Table 1. Functionalization of polymer-coated nanobeads 1 with quaterna-
ry ammonium ions under microwave heating.
are on par with or in some cases slightly higher than those
reported in the literature[23] and those of commercially avail-
able Amberlite IRA-400 and Amberlyst A-26 resins func-
tionalized with borohydride ions (2.5–3.3 mmolgÀ1). While
TEM images of pristine Co/C or Fe/C nanoparticles and pol-
ymer-coated nanoparticles 1 clearly differ due to the addi-
tional polymer shell around the nanobeads, no substantial
changes are apparent when 1 is compared to functionalized
mBER resin 4. This demonstrates the stability of the
carbon-coated nanobeads during microwave functionaliza-
tion at elevated temperature.[26]
Entry
Particles
DMF co-solvent
T
[8C]
t
DoF
[%][a]
1
2
3
4
Fe/C
Fe/C
Co/C
Co/C
Co/C
Fe/C
yes
yes
yes
no
no
no
25[b]
140
150
150
150
150
2 days
30 min
10 min
10 min
15 min
15 min
91
95
90
93
97
98
5[c]
6[c]
[a] Degree of functionalization, determined by nitrogen elemental analy-
sis. [b] No microwave irradiation applied. [c] Scale: 1 g.
To demonstrate the versatility, efficiency and recyclability
of the magnetic borohydride resin, a series of different sub-
strates was reduced by stirring with 1.5 equiv of mBER 4 in
methanol for 2-3 h (Table 2). Aromatic as well as aliphatic
aldehydes were readily reduced to the corresponding alco-
shorten reaction times (Table 1, entries 2–6). The higher
pressures of up to 15 bar due to gaseous trimethylamine and
temperatures above the boiling point of ethanol were toler-
ated by the microwave oven and the glassware alike. A con-
trol experiment without the co-solvent DMF led to an even
higher degree of functionalization (93%, Table 1, entry 4)
compared to the experiment with added DMF (90%,
Table 1, entry 3). Under optimized conditions (1508C,
15 min, no DMF) the benzyl chloride moieties were substi-
tuted almost quantitatively regardless of whether polystyr-
ene-coated Co/C or Fe/C nanoparticles were used (Table 1,
entries 5 and 6).
Table 2. Reduction of aldehydes, ketones and a,b-unsaturated substrates
with Fe/C–mBER (4) in methanol.
The progress of the functionalization was again conven-
iently monitored by ATR-IR (Figure 2). The characteristic
benzyl chloride peak at 1263 cmÀ1 vanished completely upon
nucleophilic substitution by the amine, and after stirring
with an aqueous solution of sodium borohydride for 4 h
characteristic peaks for the borohydride counterion (2203
and 1070 cmÀ1) appeared. Elemental microanalysis revealed
that 99% of the chlorine was substituted by this ion ex-
change, and the reducing capacity of the novel mBER resin
4 was determined by a 1H NMR assay with an excess of 4-ni-
trobenzaldehyde as substrate and 4-methoxyanisole as inter-
nal standard.[26] The obtained loadings (up to 3.3 mmolgÀ1)
Entry
Substrate
Product (5a–e)
t
Yield
[%][a]
[h]
1
2
2
3
88
89
3
4
5
2
3
3
88
98
99
[a] Yields of isolated compounds. Purity >95% in all cases, as deter-
mined by NMR spectroscopy.
hols in high yields and purities (Table 2, entries 1–3), and
also ketones are amenable for reduction by 4 (Table 2, en-
tries 4 and 5). Notably, when using an a,b-unsaturated
ketone the carbonyl group was reduced selectively leaving
the double bond untouched (Table 2, entry 5). The activity
and selectivity of 4 is consistent with literature reports on
polystyrene-based borohydride resins.[23] However, in con-
trast to these conventional beads, the spent mBER can be
collected by a magnet within seconds (Figure 1). To obtain
the pure product in solution the supernatant was conven-
iently decanted and the particles were washed by re-sus-
pending in methanol. Usually, more than 99.7 wt% of the
nanoparticles was recovered after drying under vacuum. To
Figure 2. IR-ATR spectra of polymer-coated Fe/C nanobeads bearing
chloro moieties (1, top), after conversion to quaternary ammonium ions
(3, middle) and subsequent exchange of the chlorine counterion with bor-
ohydride (4, bottom).
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Synthesis of Trisubstituted Ureas
FULL PAPER
Table 3. Introduction of aldehyde functionalities onto magnetic nanoparticles by nu-
cleophilic substitution under microwave heating.
prevent line broadening in the NMR spectrum due
to trace amounts of magnetic material, in some
cases additional filtration of the product solution
was nevertheless necessary.[26] The spent resin was
washed with aqueous sodium hydroxide followed
by aqueous sodium chloride to regenerate the
chlorine form 3 of the resin, while stirring with a
borohydride solution finally restored the mBER 4.
An NMR assay of the recycled resin 4 revealed
loadings (2.5–3.3 mmolgÀ1) that were comparable
to that of pristine mBER 4 and thus indicated effi-
cient recharging. The recycled resin 4 was applied
for the next run without apparent cross contamina-
tion.
Entry
Particles
T
[8C]
Microwaves
t
DoF
[%][a]
1
2
Fe/C
Fe/C
Co/C
Co/C
80
no
3 days
5 min
5 min
15 min
73
89
89
98
130
130
140
yes
yes
yes
3
4[b]
[a] Degree of functionalization, determined by chlorine elemental analysis. [b] Scale:
1 g.
Preparation of a magnetic Wang aldehyde resin
(mWang): With mBER resin 4 in hand, a magnetic
scavenger for reductive amination was synthesized
next. While several polymer-based scavengers for
amines are known in the literature,[29] the Wang al-
dehyde resin is one of the most frequently used. It
has been successfully employed for sequestration of
primary amines in the presence of secondary
amines,[21,22,30] in the synthesis of 2,3-dihydro-4-pyri-
dones[31] and, more recently, in the synthesis of a,a-
disubstituted amino acid derivatives.[32] This resin is
also commercially available nowadays on the multi-
gram scale.
Table 4. Reversible scavenging of primary amines by mWang resin 6.
Entry
Run
Amine
Loading[a]
[mmolgÀ1
Yield
[%]
Loading
N
]
after hydrolysis[a]
AHCTUNGTERNNUNG ]
[mmolgÀ1
1
2
3
1
1
1
1.91
1.97
1.94
88
89
88
0.01
0.03
0.01
For the preparation of the magnetic variant 6 of
the Wang aldehyde resin (mWang) a modified mi-
crowave synthesis[32] was used to efficiently func-
tionalize nanobeads 1 (Table 3). A control experi-
ment under thermal conditions with 4-hydroxybenz-
4
1
2.00
98
0.05
ACHTUNGTRENNUNGaldehyde as nucleophile and Cs2CO3 as a base only
5
6
7
1
2
3
2.06
2.19
2.19
94
99
99
0.02
0.03
0.04
resulted in a moderate conversion of 73% after stir-
ring at 808C for 3 d (Table 3, entry 1). Microwave
irradiation and increasing the temperature to 1308C
drastically speeded up the transformation, which
reached 89% Cl displacement after only 5 min re-
gardless of whether cobalt or iron nanoparticles
were used (Table 3, entries 2 and 3). By increasing
the temperature to 1408C and the reaction time to
15 min, almost quantitative functionalization was
achieved for a batch of 1 g. This demonstrates the effective-
ness of this microwave transformation (Table 3, entry 4).
Considering the gain in molecular mass during this function-
alization, the loadings determined by chlorine elemental
analysis (2.5–2.7 mmolgÀ1) are excellent and on par with
those of commercially available Wang aldehyde resins (up
to 3.0 mmolgÀ1), despite the metal core of the hybrid mate-
rial. TEM analysis revealed no noticeable differences be-
tween polystyrene-coated nanoparticles 1, the mBER var-
iant 4 and the mWang resin 6.[26]
[a] Loading determined by nitrogen elemental analysis.
loadings (1.9–2.2 mmolgÀ1) corresponding to yields of 89–
99%, as determined by nitrogen elemental analysis. These
results are considerably better than those for conventional
Wang aldehyde polystyrene resin, for which yields of 59–
82% are obtained for a comparable series of amines.[22] Sub-
sequently, the spent mWang resin 6 was regenerated by stir-
ring 7 with aqueous HCl in THF/H2O overnight followed by
several washing cycles with water, methanol and acetone.
The loadings of residual imine after hydrolysis were at the
detection limit of elemental microanalysis (0.01–
0.05 mmolgÀ1), which indicates quantitative cleavage.
To test the scope and effective loading of the new magnet-
ic scavenger an excess of various benzylic and aliphatic pri-
To demonstrate the recyclability of the mWang 6, the
cycle of immobilization and hydrolysis was repeated thrice
(Table 4, entries 5–7). While the loading with imine in-
creased from 94 to 99% in the second cycle, the loadings
mary amines was heated to reflux with
6 overnight
(Table 4). Resin-supported imines 7 were generated in high
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Reductive amination with mBER and mWang: The combi-
nation of these two recyclable resins was probed next in the
synthesis of a small library of secondary amines by reductive
amination of various aldehydes. To allow complete forma-
tion of the intermediary imines, aromatic or aliphatic alde-
hydes were stirred with an excess (1.5 equiv) of primary
amine in dry MeOH for three hours at room temperature
(Scheme 2). The imines were readily reduced to secondary
amines 8a–h by adding an excess of mBER resin 4 and con-
tinuing stirring overnight. In some literature reports on re-
ductive amination with conventional polystyrene reagents,[22]
MeOH turned out to be not effective, so a 1:1 mixture of
MeOH and CH2Cl2 was applied instead. In our case, howev-
er, adding CH2Cl2 slowed down the reduction noticeably
and no conversion to the secondary amines 8 was observed
when pure CH2Cl2 was used. By using MeOH and mBER 4
we were able to decrease the excess of reducing reagent
from 2.5 to 1.5 equivalents and the reaction time from 48 to
16 h. The spent resin was efficiently collected by a magnet,
washed and recycled for the next run, as described above.
To obtain pure product solutions the initial excess of pri-
mary amine had to be removed from the reaction mixtures.
Selective and complete sequestration was achieved by heat-
ing to reflux with mWang resin 6 in CH2Cl2 for 5 h
(Scheme 2). After simple magnetic decantation, washing of
the particles and evaporation of the solvent, the remaining
secondary amines 8a–h were obtained in good yields (49–
99%) and purities (all >95% by NMR; Table 5). In some
cases, however, filtration over cotton was necessary to
remove traces of magnetic material before acquiring the
NMR spectrum. The spent mWang scavenger 7 was regener-
ated by hydrolysis with aqueous HCl, as described above,
Figure 3. IR-ATR spectra of mWang resin 6 (top), after immobilization
of benzylamine (middle) and subsequent hydrolysis with aqueous HCl
(bottom). The spectra of 6 before and after one cycle coincide perfectly,
indicating complete regeneration of the aldehyde scavenger.
after hydrolysis remained at a negligibly low level. Addition-
al qualitative analysis of the functionalization and cleavage
was provided by ATR-IR analysis (Figure 3). In the spec-
trum of mWang resin 6,
a dominant broad peak at
1676 cmÀ1 can be assigned to the carbonyl group of the im-
mobilized aldehyde. After conversion to the resin-bound
imine 7, the aldehyde peak completely vanished and a new
peak appeared at 1636 cmÀ1 corresponding to resin-bound
imine groups. After the aldehyde groups were restored by
hydrolysis of the imine, the obtained spectrum (Figure 3,
bottom) perfectly matched that of as-prepared mWang resin
6 (Figure 3, top), underlining the good recyclability of the
resin.
Scheme 2. Combination of mBER 4 and mWang resin 6 for the reductive amination of aldehydes leading to secondary amines 8a–h.
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Synthesis of Trisubstituted Ureas
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Table 5. Small library of secondary amines 8a–h synthesized by reductive
amination of various aldehydes.
electron-withdrawing groups (8g, Table 5, entry 7) was per-
fectly tolerated. Also, no racemization was observed when
using enantiopure primary amines (8e, Entry 5). Additional-
ly, scale-up to 1.5 mmol of aldehyde and 2.3 mmol of amine
was carried out for 8a with an equally good yield of 96%.[26]
Entry
Primary amine
Product
Yield
[%][a]
Purity
[%][b]
1
2
97
96
>95
>95
Synthesis of trisubstituted (thio)ureas by using magnetic
resins: As the third step in the sequence, secondary amines
8 were converted to trisubstituted (thio)ureas by stirring
with an excess (1.25 equiv) of isocyanate or isothiocyanate
in CH2Cl2 for 1 h (Scheme 3). To remove the excess of re-
agent from the products 9a–e, a second magnetic scavenger
was used. The polymer-coated magnetic nanobeads func-
tionalized with benzylic amine (2), which are accessible by
Gabriel synthesis (Scheme 1), readily sequestered the excess
3
4
91
95
>95
>95
of isoACTHUNRTGNEUNG(thio)cyanate upon further stirring for 2 h. By applying
5
6
80
97
> 95
>95
an external magnet to the side of the reaction vessel
(Figure 1) the entire magnetic scavenger was collected
within seconds and the product solution decanted. After
several washing steps and evaporation of the solvents, the
pure products 9a–e were isolated in high yields (92–99%)
and purities (>95% by NMR) without the need for further
purification (Scheme 3). Aromatic (9a) and aliphatic (9b,
9c) isocyanates were applicable in this transformation in-
cluding strongly hindered ones (9c), and isothiocyanates
(9d, 9e) worked equally well (Scheme 3). No limitations
arose from the choice of amine regardless of whether diben-
zylic or monobenzylic secondary amines were used, and
scales of up to 1.4 mmol amine were successfully tested.[26]
In contrast to the other two magnetic resins, this scavenger
cannot be recycled due to irreversible formation of resin-
bound (thio)urea.
7[c]
99
49
>95
>95
8[c]
[a] Yields of isolated compounds. [b] Determined by NMR spectroscopy.
[c] No need for scavenging due to the low boiling point of the amines.
and reused in the next run
without apparent cross-con-
tamination (Scheme 2).
To demonstrate the broad
reaction
scope,
benzylic
(Table 5, entries 1–5) and ali-
phatic (Table 5, entries 6–8)
primary amines were treated
with aromatic (Table 5, en-
tries 1–3, 6 and 7) or aliphatic
(Table 5, entries 4 and 5) alde-
hydes. In only two cases was
the obtained yield below 90%:
When a long-chain aliphatic al-
dehyde was used (Table 5,
entry 5), which is known to be
a
difficult substrate,[22] and
when using an aldehyde with a
strongly acidic group (Table 5,
entry 8), which might result in
product loss due to protona-
tion of the resin and binding
by electrostatic interactions.
An aromatic alcohol that lacks
Scheme 3. Synthesis of a small library of trisubstituted (thio)ureas 9a–e by using magnetic amine 2 as scaveng-
er of excess reagent.
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O. Reiser et al.
2906, 2845, 1636, 1567, 1506, 1477, 1439, 1417, 1362, 1147, 808 cmÀ1; ele-
mental analysis (%) found: C 47.95, H 4.65, N 5.72, Cl 0.58.
Conclusion
Preparation of polymer-coated nanobeads bearing quaternary ammonium
ions (3): Polystyrene-coated iron nanobeads 1 (1.0 g, 3.5 mmol of benzyl
chloride moieties) were introduced into a microwave vial followed by the
addition of trimethylamine solution (17 mL; 4.2m in EtOH). The slurry
was stirred for 15 min at 1508C under microwave heating. The particles
were collected by using an external magnet, washed with acetone (3ꢃ
5 mL) and Et2O (2ꢃ5 mL), and dried under vacuum to give the function-
We have demonstrated the efficient synthesis of three novel
magnetic reagents and scavengers based on Co/C or Fe/C
nanoparticles, which are produced from low-cost raw mate-
rials and are commercially available on a kilogram scale.
The highly loaded magnetic resins were prepared by sur-
face-initiated polymerization followed by quantitative func-
tionalization under microwave irradiation. The progress of
the syntheses was conveniently monitored by ATR-IR spec-
troscopy, and TEM analysis showed no noticeable differen-
ces between the various magnetic resins. The highly magnet-
ic core of the hybrid material allowed rapid recovery of the
resin from reaction mixtures by an external magnet followed
by convenient decantation of the product solution.
The magnetic borohydride exchange resin (mBER) was
subsequently tested in the reduction of various aldehydes,
ketones and a,b-unsaturated substrates leading to the corre-
sponding alcohols in excellent yields and purities. The mag-
netic Wang aldehyde scavenger (mWang) was successfully
applied in the reversible sequestration of primary amines.
Next, both magnetic resins were applied consecutively in
the reductive amination of aldehydes. The imines formed by
stirring aldehydes with an excess of primary amines were
readily reduced by mBER, and the residual primary amines
selectively scavenged by the mWang resin. A small library
of secondary amines was synthesized in good to excellent
yields and excellent purities. Apart from magnetic decanta-
tion, no additional purification steps were needed, and the
resins were recycled for eight consecutive runs with different
substrates without noticeable cross-contamination. The sec-
ondary amines were converted to trisubstituted (thio)ureas.
alized beads 3 (1.14 g; loading: 2.9 mmolgÀ1). IR (ATR): n=3371, 3021,
~
2919, 2852, 2769, 1612, 1511, 1475, 1418, 1218, 974, 888, 823 cmÀ1; ele-
mental analysis (%) found: C 53.58, H 6.19, N 4.00, Cl 5.44.
General procedure for the preparation of magnetic borohydride resin
mBER (4): Polymer-coated iron nanobeads bearing quaternary ammoni-
um ions 3 (1.09 g, 3.3 mmol) were dispersed in water (15 mL) by stirring
for 10 min. Then, a solution of NaBH4 (372 mg, 9.9 mmol) in H2O
(10 mL) was added dropwise and stirring was continued for 4 h. The par-
ticles were recovered by magnetic decantation, washed with H2O (3ꢃ
20 mL) and MeOH (20 mL), and dried under vacuum for at least 5 h to
give borohydride-functionalized nanobeads 4 with a borohydride loading
of 3.0 mmolgÀ1. IR (ATR): n= 3014, 2910, 2280, 2203, 1610, 1510, 1475,
~
1418, 1376, 1071, 972, 885, 820 cmÀ1; elemental analysis (%) found: C
55.77 C, H 6.58, N 4.08, Cl 0.1.
General procedure for the synthesis of magnetic Wang aldehyde mWang
(6): Polystyrene-coated cobalt nanobeads 1 (500 mg, 1.75 mmol of benzyl
chloride moieties) were stirred in dry DMF (8 mL) under a nitrogen at-
mosphere in a microwave vessel. Subsequently, 4-hydroxybenzaldehyde
(427 mg, 3.5 mmol) and Cs2CO3 (1.71 g, 5.25 mmol) were added and the
slurry was heated to 1408C for 15 min in a focussed microwave oven.
The particles were recovered by magnetic decantation and thoroughly
washed with H2O/MeOH/acetone (1/1/1, 3ꢃ5 mL), MeOH/acetone (1/1,
3ꢃ5 mL), acetone (3ꢃ5 mL), CH2Cl2 (3ꢃ5 mL) and Et2O (1ꢃ5 mL).
After drying under vacuum for 5 h mWang resin 6 (601 mg) with a load-
ing of 2.5 mmolgÀ1 was obtained. IR (ATR): n=2919, 2845, 2726, 1683,
~
1596, 1506, 1422, 1379, 1249, 1212, 1155, 991, 814 cmÀ1; elemental analysis
(%) found: C 63.55; H 4.90, N 0.05; Cl 0.22.
Reductive amination of aldehydes with mBER and mWang resins: Alde-
hyde (0.5 mmol) and an excess of primary amine (0.75 mmol) were stir-
red in dry methanol (2 mL) under a nitrogen atmosphere for 3 h in a
flame-dried Schlenk tube. Then, mBER resin 4 (250 mg, 0.75 mmol) was
added to the reaction mixture and the stirring was continued for 16 h.
The particles were recovered by magnetic decantation, washed with
MeOH (3ꢃ3 mL) and the combined solutions were evaporated to dry-
ness. Then CH2Cl2 (5 mL) and mWang resin 6 (200 mg, 0.5 mmol) were
added and the slurry was heated to reflux at 508C for 5 h. The product
solution was decanted with the aid of a magnet and the resin was washed
with CH2Cl2 (3ꢃ5 mL). Evaporation of the solvent resulted in pure sec-
ondary amines 8a–h in high yields. Before NMR analysis, some CDCl3
solutions had to be filtered over cotton. Both magnetic resins were regen-
erated by following the general procedures described above.
The excess of isoACHTUNGTRENNUNG(thio)cyanate used was scavenged by a
third magnetic resin bearing amino groups, giving excellent
yields and purities of ureas and thioureas.
The successful demonstration of this multistep synthesis
applying exclusively magnetic reagents and scavengers
opens new possibilities for reaction automatization such as
magnetic flow reactors, which are under investigation in our
laboratories.
General procedure for synthesis of trisubstituted ureas 9a–e: In a flame-
dried Schlenk tube secondary amine 8 (0.4 mmol) and isocyanate or iso-
thiocyanate (0.5 mmol) were dissolved in dry CH2Cl2 (3 mL). The mix-
ture was stirred at room temperature under a nitrogen atmosphere for
2 h. Amine-functionalized magnetic polymer beads 2 (83 mg, 0.25 mmol)
were added and stirring was continued for 2 h. The resin was collected by
using an external magnet, the solution was decanted, and the beads were
washed with CH2Cl2 (3ꢃ5 mL). Evaporation of the combined solutions
yielded trisubstituted ureas 9a–e in excellent purities.
Experimental Section
Synthesis of polymer-coated nanobeads bearing amino groups (2): Poly-
styrene-coated iron nanobeads 1 (1.0 g, 3.0 mmol of benzyl chloride moi-
eties) were heated with potassium phthalimide (5.6 g, 30 mmol) in dry
DMF (30 mL) under a nitrogen atmosphere in a microwave reactor to
1308C for 5 min. After the mixture had cooled to room temperature, the
particles were recovered by using magnet, washed with H2O (2ꢃ30 mL),
MeOH (2ꢃ30 mL), acetone (2ꢃ30 mL) and CH2Cl2 (2ꢃ30 mL), and
~
dried under vacuum. IR (ATR): n=2918, 2845, 1770, 1705, 1510, 1388,
1325, 1081, 934, 802, 713 cmÀ1
.
Acknowledgements
The phthalimide-functionalized particles were stirred in a refluxing mix-
ture of hydrazine monohydrate (16 mL) and EtOH (64 mL) overnight.
After magnetic decantation, the amine particles 2 were washed with H2O
(3ꢃ30 mL), MeOH (3ꢃ30 mL) and CH2Cl2 (3ꢃ30 mL), and dried under
We gratefully acknowledge the International Doktorandenkolleg NANO-
CAT (Elitenetzwerk Bayern), the Deutsche Forschungsgemeinschaft
(DFG) (Re 948/8-1, ꢄꢄGLOBUCAT’’) and the EU-Atlantis program
~
vacuum to give the product resin 2 (952 mg). IR (ATR): n = 3347, 3290,
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Synthesis of Trisubstituted Ureas
FULL PAPER
CPTUSA-2006-4560 for funding this research. We thank Turbobeads Llc
for generously providing the magnetic nanobeads.
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Received: January 30, 2013
Revised: April 22, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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