Polymer 64 (2015) 221e226

Contents lists available at ScienceDirect

Polymer
journal homepage: www.elsevier.com/locate/polymer

A novel multicomponent reaction and its application in sequence-

ordered functional polymer synthesis
Ze Zhang a, Ye-Zi You a, De-Cheng Wu b, Chun-Yan Hong a, *
a
CAS Key Lab of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026,
Anhui, PR China
b
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China

a r t i c l e i n f o a b s t r a c t

Article history: Multicomponent reactions are of substantial significance not only for organic synthesis but also for
Received 22 September 2014 polymer synthesis due to their more bond-forming events per synthetic operation. Generally due to that
Received in revised form there are two or more reactions in one multicomponent reaction system, synergistic catalysis, in which
2 December 2014
the two or more reactions are activated by two or more different catalysts at the same time, is very
Accepted 12 December 2014
Available online 19 December 2014
important for achieving high-efficiency transformations. However, achieving synergistic catalysis via
using two or more different catalyst simultaneously is a great challenge. Here, we propose a new
reactant-synergistically catalyzed multicomponent reaction, in which the units coming from the reactant
Keywords:
Multicomponent reaction
can synergistically catalyze the two reactions at the same time. Moreover, this multicomponent reaction
Michael addition reaction can be extended to multicomponent polymerization, which is a very promising method for the prepa-
Ring-opening ration of functional polymers with defined-sequence.
© 2014 Elsevier Ltd. All rights reserved.

1. Introduction
Recently, one of the most attractive strategies in organic syn-
thesis is the use of one-pot multi-step operation to tailor densely
functionalized targets starting from simple precursors. This
method is widely adopted by nature, but in artificial organic
synthesis, complex target molecules are usually constructed by
stepwise formation of the individual bond in the structure of
target molecules [1e3]. Multicomponent reaction allows for more
bond-forming events per synthetic operation, enabling more
step- and time economical conversion of simple starting materials
to complex targets, which is a powerful strategy to create mo-
lecular diversity and complexity from simple and readily available
substrates in one-pot process [4e10]. Multicomponent reactions
(MCRs) are not only reactions between three or more reactants
yielding single products, such as Strecker reaction [11], the Ugi
reaction [12], the van Leusen reaction [13], the Biginelli reaction
[14], the Passerini reaction [15], the Hantzsch reaction [16],
organometallic multicomponent reactions [17,18], etc, but also
tandem (or cascade) and sequential reactions [19e21], such as
Cu-catalyzed three-component-reaction between alkynes,
* Corresponding author.
E-mail address: hongcy@ustc.edu.cn (C.-Y. Hong).
amines, and azides, etc. All these multicomponent reactions have
offered the advantages of simplicity, synthetic efficiency, syn-
thetic convergence, and atom economy for the syntheses of
complex target molecules. Though multicomponent reactions
have become increasingly popular as tool for the rapid generation
of small-molecule libraries, to ensure sufficient molecular di-
versity and complexity, it is still a cutting-edge goal to develop
novel multicomponent reactions to approach the ideal chemical
reaction [1,22]. On the other hand, although multicomponent
reactions have been used as powerful tools in complex molecule
design, drug discovery and so on, the application of multicom-
ponent reactions in polymer synthesis is still in its infancy to date
[19e21,23e25], most of the polymers prepared via multicompo-
nent reactions do not have high molecular weight, and have
limited scope of monomers. Thus, there is a continuous need to
develop new high-efficiency multicomponent reactions, via
which polymers with high molecular weight can be prepared
using a broad range of functional monomers under mild reaction
conditions [24e30].
Here, we report a multicomponent reaction with the conver-
sion up to ~100% in very mild conditions based on sequential ring-
opening of thiolactone and thiol-Michael addition reaction. Most
important, one reactant can act as catalyst to activate the
reactions in this system, therefore, additional catalysts are not
necessary. Furthermore, due to its high efficiency, this

http://dx.doi.org/10.1016/j.polymer.2014.12.012
0032-3861/© 2014 Elsevier Ltd. All rights reserved.
222 Z. Zhang et al. / Polymer 64 (2015) 221e226

multicomponent reaction is a powerful method for the prepara- 2.2.3. Mass spectrum measurement
tion of series of sequence-ordered functional polymers with high MS analysis was performed by using a LC-MS instrument
molecular weight. (Thermo Scientific, LTQ Orbitrap XL). The system was equipped
with a plus APCI source. MS data were processed using Xcalibur
software (2.1.0 SP1 built 1160).
2. Experimental section
2.3. Syntheses
2.1. Materials
2.3.1. Synthesis of N-acetohomocysteine thiolactone
N,N-Dimethyl-1,3-propanediamine (DMPDA, 99%) and benzyl
DL-Homocysteine thiolactone hydrochloride (3.07 g, 20 mmol)
azide (94%) were purchased from Alfa Aesar. DL-Homocysteine
and triethylamine (9.70 g, 96 mmol) was added in 50 mL of
thiolactone hydrochloride (99%), propargylchloroformate (96%),
dichloromethane to form a suspension in ice bath. Acetyl chloride
acetyl chloride (98%), N,N,N0 ,N00 ,N00 -pentamethyldiethylenetriamine
(2.36 g, 30 mmol) was added dropwise within 30 min. Then, the
(PMDETA, 99%), methanol-d4 (99.5 atom% D) and 4,7,10-trioxa-
solution was stirred overnight at room temperature. The reaction
1,13-tridecanediamine (97%) were purchased from SigmaeAldrich.
mixture was diluted with 20 mL dichloromethane, filtered, washed
Allylchloroformate (98%), 2-methoxypropene (95%) and N,N-bis
with brine (30 mL  2). The organic layer was dried with anhydrous
(3-aminopropyl)-ethylenediamine (98%) were purchased from
Na2SO4. Further purification can be achieved by silica gel column
TCI. Cysteamine hydrochloride (98%), triethylamine (99.5%), p-tol-
chromatography using ethyl acetate to obtain the product as white
uenesulfonic acid monohydrate (PTSA, 98.5%), benzoin dimethyl
powder. Yield was 65%. 1H NMR spectrum (300 MHz, CDCl3):
ether (DMPA, 99%), bisphenol A glycerolate dimethacrylate (re-
d 1.931 (m, 1H), d 2.029 (s, 3H), d 2.895 (m, 1H), d3.301 (m, 2H),
agent grade) and 1-butanethiol (99%) were purchased from
d 4.527 (m, 1H), d 6.171 (s, 1H).
Aladdin. Ethyl trifluoroacetate (99%) and tetrahydrofuran-d8 (99.5
atom% D) were purchased from Acros Organics. DMSO-d6 (99.8
2.3.2. Synthesis of prop-2-yn-1-yl (2-oxotetrahydrothiophen-3-yl)
atom% D) and chloroform-d (99.8 atom% D) were purchased from
carbamate
J&K. Benzylamine (98.5%), cuprous bromide (98.5%), ethanolamine
DL-Homocysteine thiolactone hydrochloride (1.54 g, 10 mmol)
(99%), sodium sulfate anhydrous (99%), sodium hydroxide (96%), n-
was added to a suspension of NaHCO3 (4.2 g, 50 mmol) in H2O/1,4-
hexane (97%), ethyl acetate (99.5%), methanol (99.7%) and diethyl
dioxane (v/v, 1/1, 20 mL), and the mixture was stirred for 30 min.
ether anhydrous (99.7%) were purchased from Sinopharm Chemical
Propargylchloroformate (2.37 g, 20 mmol) was then added drop-
Reagent Co. Ltd. (SCRC). Tetrahydrofuran (SCRC, 99%) was purified
wise within 10 min, and the mixture was stirred overnight at room
by distilling to remove H2O. Molecular sieves (5 Å) (SCRC) was
temperature. Brine (50 mL) was added into the reaction mixture,
active in muffle furnace at 400  C for 6 h. Ethylene glycol dime-
subsequently, the mixture was extracted with ethyl acetate
thacrylate (SigmaeAldrich, 98%) and methyl methacrylate (SCRC,
(70 mL  4). The organic layer was dried with anhydrous Na2SO4.
98%) were purified by small Aluminum oxide (basic) chromatog-
Further purification can be achieved by silica gel column chroma-
raphy to remove inhibitor.
tography using hexane/ethyl acetate (v/v, 1/1) to obtain the product
as slight yellow viscous oil. Yield was 53%. 1H NMR spectrum
2.2. Characterizations (300 MHz, CDCl3): d 2.034 (m, 1H), d 2.501 (s, 1H), d 2.889 (m, 1H),d
3.324 (m, 2H), d 4.343 (m, 1H), d 4.718 (s, 2H), d 5.373 (s, 1H).
All NMR spectra were recorded on a Bruker AV300 NMR spec-
trometer (resonance frequency of 300 MHz for 1H and 75 MHz for 2.3.3. Synthesis of N-(allyloxy)carbonylhomocysteine thiolactone
13
C) operated in the Fourier transform mode. The samples were DL-Homocysteine thiolactone hydrochloride (3.07 g, 20 mmol)
dissolved with chloroform-d, methanol-d4, tetrahydrofuran-d8 or was added to a suspension of NaHCO3 (8.42 g, 0.1 mol) in H2O/1,4-
DMSO-d6 and the solutions were measured with tetramethylsilane dioxane (v/v, 1/1, 50 mL) and the mixture was stirred for 30 min.
(TMS) as an internal reference. Allylchloroformate (4.85 g, 40 mmol) in 5 mL of 1, 4-dioxane was
added within 20 min, and the reaction mixture was stirred over-
night at room temperature. Subsequently, the reaction mixture was
2.2.1. NMR traces of the three-component reaction
washed with brine (100 mL) and extracted with ethyl acetate
Methyl methacrylate (20 mg, 0.2 mmol), N-acetohomocysteine
(150  3 mL). The organic layer was dried with anhydrous Na2SO4.
thiolactone (31.9 mg, 0.2 mmol) and DMPDA (30.6 mg, 0.3 mmol)
Further purification can be achieved by silica gel column chroma-
were dissolved in 0.5 mL DMSO-d6 in a NMR tube filled with argon.
tography using CH2Cl2/MeOH (v/v, 49/1) to obtain the product as
Then the tube was kept static at room temperature. 1H NMR and 13C
viscous oil. Yield was 47%. 1H NMR spectrum (300 MHz, CDCl3):
NMR spectra were recorded after appropriate time intervals.
d2.018 (m, 1H), d 2.886 (m, 1H), d 3.299 (m, 2H), d 4.338 (m, 1H),
Conversion was calculated according to the equation of
d 4.583 (d, 2H), d 5.216-5.353 (m, 3H), d 5.930 (m, 1H).
conversion ¼ ðI1  3I2 Þ=I1  100%, where I1 denotes the protons
integral values of methyl unit of methyl methacrylate; I2 denotes
2.3.4. Multicomponent reaction
the proton integral value of unreacted double bonds of methyl
The reactions were carried out in DMSO at room temperature
methacrylate.
for 6 h. One of the detailed procedures is: methyl methacrylate
(200 mg, 2.0 mmol), N-acetohomocysteine thiolactone (319 mg,
2.2.2. GPC measurement 2.0 mmol) and DMPDA (306 mg, 3.0 mmol) were dissolved in 5 mL
Molecular weights and molecular weight distributions were DMSO in a tube filled with argon. Then the reaction was carried out
measured by using a gel permeation chromatography (GPC) in- at room temperature for 6 h. 1H NMR and 13C NMR spectra were
strument. The system was equipped with a PL-RI Differential recorded at different time intervals to trace the reaction.
Refractive Index detector (DRI), PL-BV 400RT Viscometer (Visc) and
a Precision Detectors PD2020 Light Scattering Detector (LS). LiBr/ 2.3.5. Sequence-order polymer syntheses
DMF solution (0.1%) with a flow rate of 1.0 mL/min was used as Ethylene glycol dimethacrylate (99 mg, 0.5 mmol), N-acetoho-
eluent. mocysteine thiolactone (159 mg, 1.0 mmol) and 4,7,10-trioxa-
 Z. Zhang et al. / Polymer 64 (2015) 221e226 223

1,13-tridecanediamine (110 mg, 0.5 mmol) were dissolved in THF

(3 mL). Then, the mixture was degassed with argon for 5 min, and
afterward the polymerization was performed at 45  C for 48 h.
Subsequently, the solution was slowly dropped into diethyl ether.
The precipitated polymer was separated by filtration and dried in
vacuum to obtain polymer 1. Yield was 79%.

3. Results and discussion

Du Prez et al. has reported that primary amines cannot react

with the electron-deficient carbonecarbon double bond of methyl
methacrylate without a catalyst [30e32], however, they are ready
to perform the ring-opening of the cyclic homocysteine thio-
lactone, releasing a thiol [33e37], while secondary and tertiary
amines cannot perform this reaction. On the other hand, the thiol
can react with methyl methacrylate very slowly without a catalyst,
but it can react with methyl methacrylate much more efficiently in
the presence of a nucleophile such as primary, secondary or tertiary
amine [38]. The three starting molecules of methyl methacrylate,
N-acetohomocysteine thiolactone and N,N-dimethyl-1,3-
propanediamine (DMPDA) were simultaneously added to one
reactor, the following would happen. DMPDA would cause the ring-
opening of N-acetohomocysteine thiolactone to give a thiol-
intermediate but not react with methyl methacrylate. The pro-
duced thiol-intermediate is very susceptible to reacting with the
double bond of methyl methacrylate via Michael addition reaction
under the catalysis of DMPDA, producing a complex target mole-
cule in one-pot [30].
We carried out the reaction of methyl methacrylate, N-aceto-
homocysteine thiolactone and DMPDA at a molar ratio of 1:1:1.5,
and used NMR spectroscopy to trace the reaction, the detailed re-
sults are shown in Fig. 1. After the complete ring-opening of thio-
lactone, the signals at 4.59 ppm (f, methine proton in N-
acetohomocysteine thiolactone) shift completely to 4.26 ppm
(Fig. 1A), NMR spectroscopy shows that DMPDA caused ring-
opening of ~90% N-acetohomocysteine thiolactone to produce a
thiol-containing intermediate in 1.5 h, and DMPDA performed the
ring-opening of ~100% N-acetohomocysteine thiolactone in 6 h
(Fig. 1). The complete ring-opening of the thiolactone was further
verified by the transformation of the lactone unit (h, chemical shift
at 205 ppm) to amide (11, chemical shift at 171 ppm), as shown by
Fig. 1. A) 1H NMR spectra for mixture of the multicomponent reaction of methyl
the 13C NMR spectrum as shown in Fig. 1B. When we used ami- methacrylate, N-acetohomocysteine thiolactone and DMPDA in DMSO-d6 at different
noethyl piperazine with tertiary amine unit instead of DMPDA, the times. B) 13C NMR spectra for the multicomponent reaction of methyl methacrylate, N-
results show that aminoethyl piperazine can also perform ring- acetohomocysteine thiolactone and N,N-dimethyl-1,3-propanediamine in DMSO-d6 at
opening of ~100% thiolactone in 6 h (Table 1). different times.

When we used benzylamine and 3-amino-1-propanol without

tertiary amine unit in the molecular structures instead of DMPDA
with tertiary amine unit, the transformations of thiolactone into
thiol-containing intermediate are only 59.2% and 88.7% in 6 h (as
shown in Table 1), respectively. But the transformation using
benzylamine and 3-amino-1-propanol will achieve ~100% con-
version if we add 4-dimethylaminopyridine into this multicom-
ponent reaction system. Based on these results, it is clear that
tertiary amine can promote the ring-opening reaction of the thi-
olactone, which is consistent with previous findings [34]. The
catalysis of tertiary amine coming from DMPDA ensures the high-
efficiency ring-opening of thiolactone in this multicomponent
reaction system.
Simultaneously, the in situ produced thiol-intermediate is very
susceptible to reacting with the double bond of methyl methacry-
late. Generally, in the thiol Michael addition to electron-deficient
carbonecarbon double bonds, catalyst of nucleophile is necessary
for achieving high efficiency, and the proton of the thiol is
abstracted to give a thiolate anion in the presence of a nucleophile.
The thiolate anion is ready to add to electron-deficient
carbonecarbon double bond, yielding the thioether as a product.
Primary, secondary and tertiary amines are nucleophiles, which can
activate the thiol-Michael addition reaction with the efficiency of
primary amine > secondary amine > tertiary amine [38]. DMPDA,
having primary and tertiary amine units, can therefore act as a
catalyst to activate the thiol-Michael addition reaction, negating
the necessity of an additional catalyst for this reaction. For the
multicomponent reaction of methyl methacrylate, N-acetohomo-
cysteine thiolactone and DMPDA, 1H NMR results show that ~90%
and ~100% double bonds of methyl methacrylates reacted with the
thiol via Michael addition reaction in 1.5 and 6 h, respectively,
based on integral ratio of the signals at 5.65 and 6.2 ppm (double
bond protons) and the signals shifting to 2.6 ppm. The 13C NMR
results show that the signals at 125.8 and 135.9 ppm (carbons of
double bond) completely shifted to 34.5 and 39.1 ppm after thiol-
Michael addition, respectively. We used aminoethyl piperazine
instead of DMPDA, the Michael addition reaction also has an effi-
ciency of ~100% in 6 h as shown in Table 1. For the multicomponent
224 Z. Zhang et al. / Polymer 64 (2015) 221e226

Table 1
The results of the multi-component reaction of methacrylates, thiolactones and amines.

Entry Methacrylate Thiolactone Amine Ring-opening conversion (%) Michael addition conversion (%)

1 100% 100%

2 100% 100%

3 100% 100%

4 100% 100%

5 100% 100%

6 100% 100%

7 88.7% 88.5%

8 59.2% 59.1%

reactions using benzylamine and 3-amino-1-propanol, only 59.1%
and 88.5% double bonds have reacted with the thiols, which is close
to conversion of ring-opening. However, it is clear that ~100% of the
in situ produced thiols have reacted with methacrylate. The com-
plete transformation of the in situ produced thiols into thioethers is
due to that primary amines unit in benzylamine and 3-amino-1-
propanol can catalyze the thiol-Michael addition reaction. Further
to identify that the primary amine in the reactant can promote the
thiol-Michael addition reaction, we prepared the thiol-intermedi-
ate. Subsequently, we carried out the reaction of the thiol-
intermediate and methyl methacrylate in the absence of amine
molecules as shown in supporting Fig. S4. In situ NMR results show
that 29.7% of the double bonds of methyl methacrylate have reacted
with thiol in 6 h (as shown in Fig. S4) while the reaction of the thiol-
intermediate and methyl methacrylate in presence of benzylamine
has an efficiency of 99.3% in 6 h. Based on above results, it is clear
that this multicomponent reaction using the molecules containing
both primary amine and tertiary amine units is reactant-catalyzed
and has a high efficiency.
Moreover, we used 2-(2-methoxyethoxy)ethyl methacrylate
(MEO2MA) and oligo(ethylene glycol) methacrylate (OEGMA) in
this system instead of methyl methacrylate, the reactions have the
efficiency of ~100% as listed in Table 1. Due to the high selectivity of
the reactions in this multicomponent system, we can easily incor-
porate functional unit into the targeting molecules. We used
N-(allyloxy) carbonylhomocysteine thiolactone and prop-2-yn-1-yl
(2-oxotetrahydrothiophen-3-yl) carbamate instead of N-acetoho-
mocysteine thiolactone in the multicomponent reaction. Similar to
the multicomponent reaction using N-acetohomocysteine thio-
lactone, these reactions also can reach ~100% conversion. Due to the
inability of the in situ generated thiol to react with the electron-rich
double bonds without radicals, alkyne unit or alkene units survive
in the targeting molecules. Therefore, this multicomponent reac-
tion has broad monomer scope.
The reaction of methyl methacrylate, N-acetohomocysteine
thiolactone and DMPDA also shows a high conversion even if we
carried out the reaction at a molar ratio of 1:1:1. The conversion of
the multicomponent reaction can reach up to ~99% in 24 h based on
in situ NMR results. We injected the reaction mixture directly into
LC-MS instrument for MS analysis, and only the peaks for the target
molecule were observed. The signal observed at 362.2 is for the
target molecule of methyl 3-((3-acetamido-4-((3-(dimethylamino)
propyl)amino)-4-oxobutyl)thio)-2-methyl propanoate
(C16H31N3O4S, 361.2 þ 1, [MþHþ], 100%) (see supporting Fig. S5),
the signal observed at 363.2 (19.6%) and 364.2 (4.2%) are originated
from the isotopic molecule of C16H31N3O4S. The high conversion is
due to the reactant-catalysis under this condition.
This multicomponent reaction can proceed highly efficiently at
room temperature, which makes it a powerful method for the
preparation of functional polymers with ordered sequences and
high molecular weights. If we use dimethacrylate (A), diamine (B)
and N-acetohomocysteine thiolactone (C) as starting monomers in
the multicomponent polymerization system, polymers with an
ACBC sequence will be obtained as shown in Scheme 1. Here, we
chose ethylene glycol dimethacrylate (or bisphenol A glycerolate
dimethacrylate) as bis(methylacrylate) (A), 4,7,10-trioxa-1,13-
tridecanediamine (or N,N-bis (3-aminopropyl)-ethylenediamine)
as diamine (B) and N-acetohomocysteine thiolactone (C) in the
three-component polymerization system with a molar ratio of
1:1:2, producing polymers with an ACBC sequence, and the mo-
lecular weight range for the obtained polymers was 10.7e48 kDa as
shown in Table 2. We chose 4,7,10-trioxa-1,13-tridecanediamine (or
N,N-bis (3-aminopropyl)-ethylenediamine) as diamine due to that
the secondary amine and ether unit can promote the ring-opening
but will not react with thiolactone [33]. Moreover, the polymers
with clickable side units (alkyne or alkene unit) could also be
prepared when prop-2-yn-1-yl (2-oxotetrahydrothiophen-3-yl)
carbamate and N-(allyloxy) carbonylhomocysteine thiolactone
 Z. Zhang et al. / Polymer 64 (2015) 221e226 225

Scheme 1. Various functional polymers with an ACBC sequence prepared via the multicomponent polymerization of bis(methacrylate)s, diamines and thiolactones.

were used in the three-component polymerization system instead 4. Conclusions

of N-acetohomocysteine thiolactone. Although the alkyne and
alkene units can readily react with thiols via the radical-mediated
thiol-yne and thiol-ene click reaction, here the thiol-intermediate
cannot react with alkyne and alkene because there is no radical
in the three-component polymerization system. On the contrary,
the thiol-intermediate can readily react with the double bond of
methyl methacrylate (via the Michael addition thiol-ene reaction)
because the amine units in the system can activate the thiol-
Michael addition reaction with the double bond of methyl meth-
acrylate. Therefore, the alkyne and alkene units can survive in the
target sequenced-ordered polymers. This three-component
polymerization also has a broad monomer scope.
The functional side groups afford these polymers with the
powerful ability to undergo further modifications. The alkyne side
group can easily click with the azide unit at room temperature. In
order to check the efficiency of further modification, we used
(azidomethyl)benzene as the model molecule to react with the
alkyne unit in the side chain of polymer via the Cu-catalyzed azide-
alkyne cycloaddition. It is clear that the methylene unit (m) at
4.6 ppm completely moved to 5.1 ppm, the new peaks for the
benzene unit (4) were at 7.2e7.4 ppm, and the methylene unit (3)
next to benzene at 5.48 ppm and the methine unit (2) at 7.56 ppm
appeared, demonstrating the effective post-modification via click
chemistry (see Supporting Fig. S12). Moreover, the polymer with
the alkene side group can be modified via radical-based thiol-ene
click chemistry.
In summary, we have reported a reactant-catalyzed multicom-
ponent reaction based on the simultaneous ring-opening of
thiolactone and thiol-Michael addition. This novel multicomponent
reaction proceeds efficiently, and it has a broad starting molecular
scope, which sufficiently enriches sufficient molecular diversity
and complexity. Moreover, this novel multicomponent reaction can
be extended to multicomponent polymerization for preparing a
series of sequence-ordered functional polymers with high molec-
ular weight. Functional side groups could be easily introduced to
the polymers by effective post-modification.
Acknowledgments
We acknowledge support from the National Natural Science
Foundation of China (51033005, 51273187, 21474097, 21374107 and
21090354), the Fundamental Research Funds for the Central
Universities (WK2060200012) and the Program for New Century
Excellent Talents in Universities (NCET-11-0882).
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.polymer.2014.12.012.
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