Synthesis and application of a microgel-supported acylating reagent by coupled ring-opening metathesis polymerization and activators Re-Generated by electron transfer for atom transfer radical polymerization

Article abstract of DOI:10.1021/cc900162w

A novel microgel-supported acylating reagent (MGAR) was prepared by combining ring-opening metathesis polymerization (ROMP) and Activators Re-Generated by Electron Transfer for Atom Transfer Radical Polymerization (ARGET ATRP): (1) synthesis of an ATRP macroinitiator 3 by living ROMP of oxanorbornene-based activated ester 1, derived from Af-hydroxysuccinimide, using the Grubbs initiator RuCl₂(PCy₃)₂(=CHPh) and (Z)-but-2-ene-l,4-diyl bis(2-bromopropanoate) (BDBP) as a terminating agent; (2) synthesis of MGAR 4 by ARGET ATRP of styrene (S) and divinylbenzene (DVB) using the prepared macroinitiator 3, a CuCI₂ZMe₆TREN (tris[2-(dimethylamino)ethyl]amine) catalyst system, a Sn(Oct)₂ [tin(II)2ethylhexanoate] reducing agent. The synthesized microgels 4 exhibit excellent acyl (acetyl, benzoyl, phenylsulfonyl) transfer properties for primary and secondary amines (n-BuNH₂, Et₂NH, morpholine, etc.) under mild conditions (25 °C, 13.5-14 h) affording N-acylamines with high yield (95.6-100%) and purity (94.1-96.0%).

Full text of DOI:10.1021/cc900162w

J. Comb. Chem. 2010, 12, 255–259
255
Synthesis and Application of a Microgel-Supported Acylating Reagent
by Coupled Ring-Opening Metathesis Polymerization and Activators
Re-Generated by Electron Transfer for Atom Transfer Radical
Polymerization
Hong Li,* Zi-Bo Pang, Zhi-Feng Jiao, and Fei Lin
Key Laboratory of Functional Polymer Materials of Education Ministry, Institute of Polymer Chemistry,
Nankai UniVersity, Tianjin 300071, China
ReceiVed October 14, 2009
A novel microgel-supported acylating reagent (MGAR) was prepared by combining ring-opening metathesis
polymerization (ROMP) and Activators Re-Generated by Electron Transfer for Atom Transfer Radical
Polymerization (ARGET ATRP): (1) synthesis of an ATRP macroinitiator 3 by living ROMP of
oxanorbornene-based activated ester 1, derived from N-hydroxysuccinimide, using the Grubbs initiator
RuCl2(PCy3)2()CHPh) and (Z)-but-2-ene-1,4-diyl bis(2-bromopropanoate) (BDBP) as a terminating agent;
(2) synthesis of MGAR 4 by ARGET ATRP of styrene (S) and divinylbenzene (DVB) using the prepared
macroinitiator 3, a CuCl2/Me6TREN (tris[2-(dimethylamino)ethyl]amine) catalyst system, a Sn(Oct)2 [tin(II)2-
ethylhexanoate] reducing agent. The synthesized microgels 4 exhibit excellent acyl (acetyl, benzoyl,
phenylsulfonyl) transfer properties for primary and secondary amines (n-BuNH2, Et2NH, morpholine, etc.)
under mild conditions (25 °C, 13.5-14 h) affording N-acylamines with high yield (95.6-100%) and purity
(94.1-96.0%).
polymers.25-28 It is also worth noting that in the field of
soluble functional polymers, the pioneering work on micro-
gel-supported organic synthesis reported by Wulff and Janda
is encouraging.29-31 Microgels are intramolecularly cross-
linked molecules in nature; interestingly they form stable
solutions of low viscosity in suitable solvents. At this point,
microgels are the clever hybrids of insoluble and soluble
polymers. The unique properties of microgels make them
seem to be more suitable candidates as soluble supports for
organic synthesis. Herein, we report the first synthesis of a
microgel-supported acylating reagent (MGAR) by coupled
ROMP and ARGET ATRP (controlled polymerization using
Activators Re-Generated by Electron Transfer for Atom
Transfer Radical Polymerization),32-34 and the application
of the microgel reagent to acylation of amines.
Introduction
In recent years the interest in polymer-supported reagents
for organic synthesis has significantly increased along with
the rapid development of the combinatorial chemistry.1,2
Typically, the insoluble polymers are the most commonly
used because of the well-known advantages such as the ease
of isolating the used polymer from a reaction mixture, the
adaptation of the supported reagents for continuous-flow
process, and so forth. However, the heterogeneous nature
of the reaction in the use of these solid phase polymers in
solution brings about some drawbacks, such as the difficulty
of monitoring the reaction process, the low accessibility of
the anchored reagents to the substrates in solution, in general
the non-linear reaction kinetics and so forth. Consequently,
soluble polymer supported reagents have recently attracted
considerable attention.3-8 The soluble polymer reagents
behave like small molecules in solution affording the normal
solution reaction kinetics, convenience in monitoring the
reaction process, higher reaction efficiency, and so forth.
Acylation of amines is one of the most commonly used
reactions in the pharmaceutical and fine chemical synthe-
sis.9-17 Ring-opening metathesis polymerization (ROMP)
proved to be a useful tool for functional polymer design;18-24
among the diversity of functional polymers synthesized by
means of ROMP over the past decade, the ROMPGEL-
supported acylating reagents reported by Barrett et al.
represent a promising category of insoluble functional
Results and Discussion
Synthesis of MGAR. The synthesis of MGAR 4 contains
two key polymerization processes (Scheme 1).
First, the ROMP of monomer 1, derived from an activated
ester, oxanorborneno-succinimidyl carboxylate, was carried
out at room temperature (RT) in dichloromethane (DCM)
using a Grubbs initiator RuCl2(PCy3)2()CHPh). Termination
of the active ruthenium carbene end of the ROM-polymer 2
with cis-2-butene-1, 4-diyl bis(2-bromopropanoate) (BDBP)
yielded a monoend R-bromoester-functionalized polymer 3
with designed number-average molecular weight(Mn). The
ROMP showed typical characteristics of living polymeriza-
tion: the formed polymers possessed narrow molecule weight
distribution (MWD) as evidenced by the polydispersity index
* To whom correspondence should be addressed. E-mail: hongli@
nankai.edu.cn.
10.1021/cc900162w  2010 American Chemical Society
Published on Web 01/14/2010

256 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Scheme 1. Synthesis of MGARa
Li et al.
Table 1. Synthesis of an ATRP Initiator of Polymer 3a by
Table 2. Synthesis of MGARs by ARGET ATRP with
ROMPa
Synthesized Macroinitiatorsa
b
[DVB]0/[S]0
mol/mol
Cdeb solubility
[M]0/[I]0 ,
entry
I
t, h MGAR Mn,GPC × 10-5 PDI
%
DMF
entry mole/mole conv.c, % Mn,th × 10-3 Mn,GPC × 10-3 PDI
1
2
3
4
5
6
3a-3
3a-3
3a-3
3a-3
3b-4
3c-3
0.20
0.20
0.30
0.40
0.20
0.20
22.0 4a-1
24.0 4a-2
24.0 4a-3
23.8 4a-4
24.0 4b
3.84
4.21
1.81 4.5
1.78 4.8
sol.
sol.
1
2
3
4
5
10
20
25
50
100
99.9
99.6
99.6
99.8
99.7
3.12
5.97
7.40
14.5
28.8
3.60
5.70
7.70
13.0
27.4
1.08
1.11
1.13
1.14
1.19
insol.
insol.
sol.
6.16
4.35
1.98 4.6
1.74 4.4
24.0 4c
sol.
a Polymerization in DCM, at RT for 20 min. b M: monomer 1a; I:
RuCl2(PCy3)2()CH-Ph). Measured by H NMR.
a 100 °C, DMF 2 mL, [I]0 ) 3.167 mmol/L; I: macroinitiator;
c
1
[S]:[I]:[CuCl2]:[Me6TREN]:[Sn(Oct)2] ) 500:1:0.01:0.1:0.1. b Cross-link-
1
ing degree quantitatively estimated by H NMR.
Figure 1. Synthesis of an ATRP Macroinitiator 3a by ROMP.
1
Figure 2. H NMR Spectrum of MGAR 4a-2
(PDI 1.08-1.19, Table 1) values, a linear relationship of
Mn,GPC (Mn measured by GPC) of formed polymers versus
the initial molar ratio of [M]0/[I]0 was observed (Figure 1,
line 2), and the determined values of Mn,GPC were approaching
the theoretically calculated values of Mn,th (Figure 1, line 2
vs 1).
Second, to prepare the MGARs the preformed polymers
3 (3a-3: Mn 7.70 × 103; 3b: Mn 1.10 × 104; 3c: Mn 8.45 ×
103, in Table 1 Entry 3, Supporting Information Table SI-1
Entry 4, Table SI-2 Entry 3, respectively) were used to
initiate an ARGET ATRP of styrene and divinylbenzene in
DMF using a CuCl2/Me6TREN catalyst system and a
reducing agent tin(II) 2-ethylhexanoate Sn(Oct)2. Under the
selected optimizing conditions ([DVB]0/[S]0 ) 0.20, 100 °C,
24 h) the target MGARs 4a-2 (Mn 4.21 × 105), 4b (Mn 6.16
× 105), and 4c (Mn 4.35 × 105) were successfully prepared
1
(Table 2, Entry 2, 5, 6). H NMR characterization demon-
strated the structure of synthesized MGARs as exemplified
by MGAR 4a-2 (Figure 2).
Experimental results indicated that the optimizing value
of [DVB]0/[S]0 was 0.20. A further increase of initial DVB
feeding led to the formation of insoluble polymers instead
of soluble microgels (Table 2, Entry 3, 4). The cross-linking
degrees of the microgel reagents were quantitatively esti-
mated to be 4.4-4.8% (Table 2) based on the H NMR
characterization of the amount of unreacted CdC bonds in
the DVB units of the microgel molecules.
1
Application and Recycle of MGAR. The synthesized
microgels 4 were applied to N-acylation of a variety of
amines (Scheme 2, Table 3).

Synthesis of a Microgel-Supported Acylating Reagent
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 257
Scheme 2. Application and Recycle of Synthesized MGARs
a macroinitiator 3, a linear functional polymer prepared by
living ROMP; the molecular geometry of the MGAR 4 is
postulated to bear a resemblance with that of star polymers
(Scheme 3). The functional groups are anchored on the naked
arms of the microgels and hence are readily accessed by
substrates in solution. This may account for the excellent
acyl transfer performance of the MGAR.
Because of the high molar mass of the synthesized
MGARs (4a-2: Mn 4.21 × 105; 4b: Mn 6.16 × 105; 4c: Mn
4.35 × 105), the used microgels 5 can be conveniently
recovered by precipitation from methanol. Treating the
recovered microgels 5 with corresponding acyl chlorides
regenerates the microgel reagents 4. On the basis of 1H NMR
characterization, the relative functionalization degrees of the
regenerated microgel reagents (Table 4, R-4a-2, R-4b, R-4c)
were quantitatively estimated to be 70.4-72.5%. The acy-
lation performance of the regenerated MGARs for amines
showed no obvious difference with that of the freshly
prepared counterparts (Table 4).
Table 3. Acylation of Amines Using Synthesized MGARsa
MGAR
amine
name
entry no. µmol
µmol time, h yield % purityb
%
1
2
3
4
5
6
7
8
9
4a-2 198 n-BuNH2
4a-2 132 Et2NH
4a-2 132 Morpholine
4a-2 133 NH2-Et-NH2 104.6
4a-2 133 p-phenetidine 100.9
152.3
96.25 14.0
103.3
13.5
100
96.1
96.7
93.7c
0
96.0
94.1
95.1
14.0
14.0
18.0
18.0
13.5
Conclusion
In summary, a new method for making microgel-supported
reagents was demonstrated. The approach involves the
following. (1) Synthesis of an ATRP macroinitiator 3, a linear
polymer bearing a side activated acyl group in the repeating
unit and a chain-end R-bromoester group, via living ROMP
with Grubbs initiator RuCl2(PCy3)2()CH-Ph). (2) To prepare
the microgel reagent 4, ARGET ATRP of styrene and
divinylbenzene using the synthesized macroinitiator was
carried out in DMF. Three kinds of acyl (acetyl, benzoyl,
phenylsulfonyl) transfer reagents supported on microgels with
high molar mass (4a-2: Mn 4.21 × 105; 4b: Mn 6.16 × 105;
4c: Mn 4.35 × 105) and narrower MWD (4a-2: PDI 1.78;
4b: PDI 1.98; 4c: PDI 1.74) were successfully prepared.
Under mild conditions the microgel reagents showed excel-
lent acylating properties for primary and secondary amines
affording the desired products with very high yield and
purity. For ethylene diamine the acylated products contami-
nated with 10.1-10.6% of bis-acylated compounds. An
attempt at acylating p-phenetidine and pyrrole (weak base
amines possessing p-π conjugation) with MGAR 4a-2 failed.
Finally, it is worth noting that the microgels can be easily
recovered after use, and the regenerated microgel reagents
showed similar acylation performance as the freshly prepared
counterparts. The results of the work presented here reveal
the promising prospect of microgel-supported reagents in
organic synthesis. To the best of our knowledge, this is the
first report on the synthesis and application of a microgel-
supported acylating reagent.
4a-2 133 Pyrrole
101.2
101.3
96.25 13.5
0
4b
4b
4b
132 n-BuNH2
133 Et2NH
133 Morpholine
98.1
96.5
97.2
93.4d
97.6
95.6
96.2
94.0e
94.7
95.3
95.4
103.3
13.8
14.0
13.5
10 4b
11 4c
12 4c
13 4c
14 4c
132 NH2-Et-NH2 104.6
132 n-BuNH2
132 Et2NH
133 Morpholine
133 NH2-Et-NH2 104.6
101.3
96.25 13.5
103.3
94.5
95.2
94.3
14.0
14.0
b
a Temp. 25 °C, THF. Based on H NMR characterization. c Product
contained monoacylated product 84.0% and bis-acylated product 9.7%.
d Product contained monoacylated product 83.5% and bis-acylated
product 9.9%. e Product contained monoacylated product 84.5% and
bis-acylated product 9.5%.
1
Acylation of primary and secondary amines (n-BuNH2,
Et2NH, morpholine, etc.) with the synthesized MGARs was
successfully carried out under mild conditions (25 °C,
13.5-14 h) in THF with a slight excess equivalency of
microgel agents yielding the desired products in high purity
(94.1-96.0%) and excellent yield (95.6-100%, Table 3).
However, the acylation products of diamine H2NCH2CH2NH2
contained a small amount of 1,2-bis-acylated compounds
(10.1-10.6% of the total yields). It is also worth noting that
an attempt at acylating p-phenetidine and pyrrole with
MGAR 4a-2 failed (Table 3, Entry 5, 6). This is possibly
because the acylation reaction of amines is a nucleophilic
substitution. A key step in the reaction is the attack of N
atoms of the nucleophilic substrates (amines) upon the
carbonyl carbons in MGAR molecules. The nucleophilicities
of nitrogen atoms in p-phenetidine and pyrrole are greatly
decreased owing to the p-π conjugation of p-lone pair
electrons of N atoms with the π-electrons in the benzene
and pyrrole rings.
Experimental Section
Materials and General Methods. All manipulations and
reactions were carried out under argon with standard Schlenk
apparatus and techniques. Grubbs complex RuCl2(PCy3)2-
()CH-Ph), N-hydroxysuccinimide(97%) and tin(II) 2-eth-
ylhexanoate were products of Sigma-Aldrich Co., BDBP was
prepared according to ref 35, and Me6TREN was synthesized
according to a literature procedure.36 Other reagents were
analytically pure and thoroughly dried before use. Dry,
The traditionally insoluble reactive polymers prepared by
copolymerization of a functional monomer and a cross-
linking agent are macroreticular beads or granules. In the
use of these polymers, a considerable portion of anchored
functional groups are difficult to access by substrates in
solution. The MGAR 4, reported herein, was prepared by
the controlled radical polymerization (ARGET ATRP) using

258 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Li et al.
Scheme 3. Plausible Pathway on the Synthesis of MGAR by Coupled ROMP and ARGET ATRP
Table 4. Reusability of the Regenerated MGARsa
was added to the mixture at RT, and stirring was kept up
for another 20 min. The polymer-containing solution was
added dropwise to a mixed solution of ethyl ether and
n-hexane (1:1, 100 mL). Filtration followed by vacuum-
drying yielded a pale brown powder 1.6252 g in 89.6% yield.
N-acylbutylamine N-acyldiethylamine
func. degreee yield
purity
(%)
yield
(%)
purity
(%)
entry microgel
mole %
(%)
1
2
3
4
5
6
4a-2
R-4a-2b
4b
100
70.4
100
71.2
100
72.5
100
96.0
94.1
94.7
93.8
94.5
94.2
96.1
94.5
96.5
94.1
93.2
95.3
1
GPC: Mn ) 7.7 × 103, Mw/Mn ) 1.13. H NMR(CDCl3,
97.0
98.1
96.3
97.6
95.8
400 MHz) δ: 3.416(br, s, 2nH), 4.373-4.438(m, 1H),
4.620-5.065(2br, 2s, (2n+2)H), 5.834-6.102(2br, 2s, 2nH),
6.299-6.353(m, 2H), 6.766-6.819(m, 1H), 7.487(br, s,
2nH), 7.650(br, s, 1nH), 8.099(br, s, 2nH).
R-4bc
4c
95.6
93.8
95.2
93.6
R-4cd
a 25 °C, 13.5 h, THF. b R-4a-2: regenerated MGAR 4a-2. c R-4b:
regenerated MGAR 4b. d R-4c: regenerated MGAR 4c. e Relative value.
Preparation of MGAR 4. The typical procedure is as
follows: Macroinitiator 3a-3 (Mn ) 7700, PDI ) 1.13,
0.2432 g, 31.67 µmol), styrene(S, 1.71 mL, 14.80 mmol)
and divinylbenzene (DVB, 550 µL, 80%, containing S 0.952
mmol and DVB 3.131 mmol) were added to DMF (10 mL).
A DMF solution of CuCl2 and Me6TREN (265 µL, [CuCl2]
) 1.1852 mmol/L, [Me6TREN]/[CuCl2] ) 10:1), and a
toluene solution of Sn(Oct)2 (50 µL, [Sn(Oct)2] ) 30.916
mmol/L) were added to the above mixture. After stirring for
24 h at 100 °C under argon, the reaction mixture was poured
into methanol (200 mL). A pale yellow powdery polymer
was precipitated and was filtered, washed with methanol,
and vacuum-dried yielding the desired microgel 4a-2 0.8017
g. GPC: Mn ) 4.21 × 105, Mw/Mn ) 1.78. 1H NMR(CDCl3,
400 MHz) δ: 0.4-2.6(br, 3.76H), 3.446(br, s, 2H), 4.640-
5.080(2br, 2s, 2H), 5.255-5.299(dd, J1 ) 10.4 Hz, J2 ) 7.2
Hz, 0.25H), 5.753-5.813(dd, J1 ) 17.6 Hz, J2 ) 6.4 Hz,
0.29H), 5.858-6.121(2br, 2s, 2H), 6.257-7.255(br, 3.81H),
6.711-6.782(dd, J1 ) 17.6 Hz, J2 ) 10.8 Hz, ∼0.25H),
7.506(br, s, 2H), 7.667(br, s, 1H), 8.113(br, s, 2H).
oxygen-free solvents were used throughout the experiments.
The molecular weights of the synthesized polymers were
determined with GPC on a Water 1525 chromatograph
equipped with a refractive-index detector and a set of three
columns (styragel HT2, HT3, HT4). The columns were
calibrated with polystyrene standards. Analysis was per-
formed with THF as a solvent at a flow rate of 1.0 mL/min.
1H NMR spectra of the samples were recorded on a Varian
Unity Plus-400 spectrometer operating at 400 HMz (1H).
Preparation of Monomer 1. The typical procedure is as
follows: An oven-dried flask was charged with N-hydroxy-
succinimide (2.03 g, 11.22 mmol) in 10 mL of DMF.
Benzoyl chloride (1.6 mL, 13.90 mmol) was added dropwise
into the flask. The mixture was stirred at 60 °C for 7 h, then
poured into 100 mL of water. The white solid was filtered
out, washed with water for three times, then vacuum-dried
at 40 °C for 24 h. A white solid (3.08 g) was obtained in
1
96.3% yield. H NMR(CDCl3, 400 MHz) δ: 2.966(s, 2H),
5.394(s, 2H), 6.559(s, 2H), 7.492-7.530(t, J ) 7.6 Hz, 2H),
7.660-7.697(t, J ) 7.6 Hz, 1H), 8.122-8.141(d, J ) 7.6
Hz, 2H).
Preparation of Macroinitiator 3. The general procedure
is as follows: Grubbs Catalyst (RuCl2(PCy3)2()CH-Ph))
(0.2094 g, 0.2544 mmol, 4 mol %) in 4 mL of CH2Cl2 was
added to a stirred solution of 1a (1.8145 g, 6.3758 mmol) in
7.5 mL of CH2Cl2. The mixture was stirred at 25 °C for 20
min. BDBP (0.7351 g, 2.0534 mmol) in 2 mL of CH2Cl2
Acylation of Amines. The general procedure is as follows:
To a solution of MGAR 4a-2 (0.1860 g, containing benzoyl
group 198.0 µmol) in 2 mL of THF n-butylamine (15 µL,
152.3 µmol) was added. Then the reaction mixture was
stirred at 25 °C for 13.5 h. Four milliliters of methanol was
added to the mixture, and the precipitated polymer was fil-
tered off, vacuum-dried to afford a pale yellow powder
(0.1575 g, 92.5% polymer recovery). The filtrate was

Synthesis of a Microgel-Supported Acylating Reagent
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 259
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N-benzoylbutylamine (27.2 mg) in 100% yield and 96.0%
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purity. H NMR(CDCl3, 400 MHz) δ: 0.955-0.992(t, J )
102, 3325–3344.
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J ) 7.2 Hz, 2H), 3.450-3.500(q, J ) 7.2 Hz, 2H), 6.084(s,
1H), 7.418-7.454(t, J ) 7.2 Hz, 2H), 7.481-7.518(t, J )
7.2 Hz, 1H), 7.753-7.771(d, J ) 7.2 Hz, 2H).
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Regeneration of MGAR 4. The general procedure is as
follows: To a solution of recovered microgel 5 (70.60 mg)
in pyridine (2 mL) benzoyl chloride (45 µL, 0.390 mmol)
was added. The mixture was stirred at RT for 24 h, then 4
mL of methanol was added into the mixture. The precipitated
polymer was filtered off, washed with cold methanol, and
vacuum-dried affording microgel R-4a-2 0.0641 g (yield:
81.75%), with a relative functionalization degree of 70%
based on 1H NMR characterization. 1H NMR(CDCl3, 400 MHz)
δ: 0.4-2.6(br, ∼3.41H), 3.425(br, s, 2H), 4.624-5.062(2br,
2s, 2H), 5.830-6.104(2br, 2s, 2H), 6.250-7.230(br, 3.45H),
7.477(br, s, 1.40H), 7.642(br, s, 0.69H), 8.084(br, s, 1.39H).
Reusability of Regenerated MGAR. The general pro-
cedure is as follows: To a solution of regenerated microgel
R-4a-2 (0.0476 g, 36.65 µmol) in THF (2 mL) was added
n-butylamine (2.7 µL, 28.20 µmol). The mixture was stirred
at 25 °C for 13.5 h, then 4 mL of methanol was added. The
precipitated polymer was filtered off and vacuum-dried to
afford a pale yellow fine powder (0.0403 g, 90.06% polymer
recovery). The filtrate was evaporated under vacuum to
remove the solvent affording N-benzoylbutylamine (0.0047
g, yield: 97.0%, purity: 94.1%). 1H NMR(CDCl3, 400 MHz)
δ: 0.946-0.983(t, J ) 7.2 Hz, 3H), 1.377-1.469(m, J )
7.2Hz,2H),1.572-1.646(m,J)7.2Hz,2H),3.441-3.491(q,
J ) 7.2 Hz, 2H), 6.114(s, 1H), 7.411-7.448(t, J ) 7.2 Hz,
2H), 7.476-7.512(t, J ) 7.2 Hz, 1H), 7.748-7.766(d, J )
7.2 Hz, 2H).
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