New click chemistry: Click polymerization via 1,3-dipolar addition of homo-ditopic aromatic nitrile oxides formed in situ

Article abstract of DOI:10.1246/cl.2008.918

New click chemistry is demonstrated. Click polymerization proceeded via 1,3-dipolar polycycloaddition of homo-ditopic nitrile oxides to bifunctional terminal olefinic and acetylenic monomers as dipolarophiles. Molecular sieves (MS 4A) served as an efficie

Full text of DOI:10.1246/cl.2008.918

918
Chemistry Letters Vol.37, No.9 (2008)
New Click Chemistry: Click Polymerization via 1,3-Dipolar Addition
of Homo-ditopic Aromatic Nitrile Oxides Formed In Situ
Yasuhito Koyama, Morio Yonekawa, and Toshikazu TakataÃ
Department of Organic and Polymeric Materials, Tokyo Institute of Technology,
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552
(Received May 2, 2008; CL-080456; E-mail: ttakata@polymer.titech.ac.jp)
New click chemistry is demonstrated. Click polymerization
HO
Cl
OH
Cl
O
O
N
O
O
N
N
N
O
Et3N (2.2 equiv)
proceeded via 1,3-dipolar polycycloaddition of homo-ditopic
nitrile oxides to bifunctional terminal olefinic and acetylenic
monomers as dipolarophiles. Molecular sieves (MS 4A) served
as an efficient promoter for the polymerization to afford poly-
isoxazolines and polyisoxazoles in high yields.
+
BuO
OBu
DMF, RT, 24 h
98%
OBu
1
2
3
Scheme 2. Reaction of bifunctional nitrile N-oxide 1 and butyl
acrylate (2).
to find the effect of base. While base-free condition6–8 (Entry 1)
proved inferior to base-promoted conditions, we found that a va-
riety of bases effectively promoted the desired polymerization in
moderate yields (Entries 2–5). In hopes of efficiently accelerat-
ing the polymerization, we sought to identify a more active base
working without any side reaction. After considerable efforts,
this goal was achieved by the addition of MS 4A as a suitable
base as well as a dehydrating agent (Entries 6–9).9–11 Polyisox-
azoline poly-5 was obtained in 99% yield by polymerization at
80 ꢀC for 1 d in the presence of 344 mg of MS 4A (vs. 0.22 mmol
of 4), giving preferentially one regioisomer (Entry 7, Mn 9100,
Mw 14900, and Mw=Mn 1.6 by GPC).12 In the present MS 4A-
containing system, higher temperature and prolonged reaction
time resulted in the decrease of yield and the lowering in molec-
ular weight, probably due to retrocycloaddition (Entries 8 and 9).
The regiochemistry of the isoxazoline moiety of poly-5 was
determined as that illustrated in Table 1 by the NOESY correla-
tion observed between the isoxazoline methylene protons and
the aromatic protons.
Recent sophisticated supramolecular and macromolecular
architectures strongly require viable means of powerful, highly
reliable, and selective reactions. For this purpose, click chemis-
try,1 exploiting the Huisgen dipolar cycloaddition of azides and
alkynes, has generated particular interest.2 Click reactions have
been actually utilized in a variety of synthetic processes for su-
pramolecules and macromolecules. However, problems of safety
with the azide moiety concerning toxicity and explosiveness lead
to several limitations to the use.3 Recognizing these issues, we
became intrigued by the potential usefulness of nitrile N-oxide
as a 1,3-dipole, which allows efficient [2 + 3]cycloaddition re-
action with not only alkenes but also alkynes to selectively give
isoxazoline and isoxazole.4,5 These hetero-rings are versatile
scaffolds for various derivatives, because they enable simple
conversion to useful functional groups; aldol, diketone, ꢀ-ami-
noalcohol, and so on. Nitrile N-oxides, however, have not been
employed to click chemistry yet.
Herein, we wish to describe affirmative answers for the
utility and productivity of new click chemistry exploiting nitrile
N-oxide, as demonstrated by the polycycloaddition reaction of
homo-ditopic aromatic nitrile N-oxide to various bifunctional
terminal olefins and acetylenes as dipolarophiles, according to
a MS 4A promoted protocol.
Scheme 1 shows the fundamental reaction scheme of the
‘‘click chemistry’’ utilizing aromatic hydroxamoyl chloride as
the precursor of reactive aromatic nitrile N-oxide. Prior to the
polymerization, a click reaction using benzene-1,3-dicarbohy-
droximoyl dichloride (1) and butyl acrylate (2) was carried out
as shown in Scheme 2. The addition product 1,3-bis(3-isoxazo-
linyl)benzene 3 was obtained in a high yield as a single diaster-
eomer, certainly suggesting the possibility of efficient polymer-
ization.
As for the versatility of monomers of this click polymeriza-
tion, terephthalohydroximoyl dichloride instead of 1 and a vari-
ety of bifunctional terminal olefinic and acetylenic monomers
could be employed, as shown in Tables 2 and 3.
Dimethacrylate 7, bisphthalimide 9, and 1,5-hexadiene (11)
with 1 underwent clean polycycloadditions (Entries 2–4).13 The
polyaddition to alkynes such as bispropiolate 13, p-diethynyl-
Table 1. ‘‘Click polymerization’’ in terms of the effect of base
HO
Cl
OH
Cl
O
O
N
N
N
N
O
O
O
O
Conditions
Solvent
O
+
O
O
O
O
O
1
4
poly-5
a
a
a
Entry Base
Solvent
Toluene
Temp/ꢀC Time/d Mn
Mw Mw=Mn Yield/%
Table 1 summarizes the results of ‘‘click polymerization’’
via polycycloaddition of 1 to a bifunctional acrylate 4 mainly
1
—
120
rt
1
1
1
1
5
7
1
8
1
3700 5500
3400 4600
4200 5700
4600 6500
5300 7800
6000 8600
9100 14900
6000 8600
6700 10100
1.5
1.3
1.4
1.4
1.5
1.4
1.6
1.4
1.5
24
99
60
60
67
90
99
86
89
2b NaOH CH2Cl2/H2O
3
4
5
6
7
8
9
Et3N
KF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
rt
O
N
rt
R1
R2
R1
KF
rt
OH
Cl
O−
N
N
Base
MS 4A
MS 4A
MS 4A
MS 4A
rt
C
O
Dipolarophiles
R2
N
80
80
100
aEstimated by GPC based on polystyrene standards. bPolymerization reaction was
carried out with NaOH (2.5 equiv) in the presence of TBAB (5 mol %).
Scheme 1. Click reaction exploiting nitrile N-oxide and olefin
or acetylene.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.9 (2008)
919
Table 2. Syntheses of polyisoxazoles and polyisoxazolines by
MS 4A-promoted polycycloaddition
performance materials. Further broad applications of this
click chemistry are currently in progress.
Entry
Dipolarophile
Products
Yield/%
99
References and Notes
H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem., Int.
Ed. 2001, 40, 2004.
N
N
O
O
O
O
O
O
O
O
1
1a
O
O
O
O
O
O
O
O
4
2
For selected reports of polymerization exploiting ditopic
azido group, see: a) D. J. V. C. van Steenis, O. R. P. David,
G. P. F. van Strijdonck, J. H. van Maarseveen, J. N. H. Reek,
Chem. Commun. 2005, 4333. b) D. D. Diaz, K. Rajagopal,
E. Strable, J. Schneider, M. G. Finn, J. Am. Chem. Soc.
2006, 128, 6056.
poly-6
O
O
N
N
O
O
O
O
2
3
99
O
O
7
poly-8
O
O
O
O
N
N
O
O
O
O
3
4
K. E. Russell, J. Am. Chem. Soc. 1955, 77, 3487.
For selected review on isoxazoles, see: S. A. Lang, Y.-I. Lin,
in Comprehensive Heterocyclic Chemistry, ed. by A. R.
Katritzky, C. W. Rees, Pergamon, Oxford, 2000, Vol. 6, p. 1.
For a related report exploiting nitrile imine as 1,3-dipolar,
see: J. K. Stille, L. D. Gotter, Macromolecules 1969, 2, 465.
Y. Iwakura, K. Uno, S.-J. Hong, T. Hongu, Polym. J. 1970,
2, 36.
For a selected report about polyisoxazolines and polyisoxa-
zoles, see: S.-J. Hong, Polymer 1973, 14, 286.
The major side pathway was a dimerization of nitrile
oxide to give a furoxane, which afforded a swelled gel,
due most likely to the crosslinking reaction of furoxane
and propagation end.
N
N
N
N
99
81
O
O
O
poly-10
9
O
N
N
5
6
7
8
4
5
6
11
poly-12
O
O
N
N
O
O
O
O
O
99
99
O
O
O
O
O
13
poly-14
O
O
N
N
15
17
poly-16
9
For a review of molecular sieve promoted reactions, see:
S. E. Sen, S. M. Smith, K. A. Sullivan, Tetrahedron 1999,
55, 12657.
O
O
N
N
80
7
10 For related reports about MS 4A promoted cycloadditon of
nirile N-oxide, see: a) J. N. Kim, E. K. Ryu, Heterocycles
1990, 31, 1693. b) U. Pindur, M. Haber, Heterocycles
1991, 32, 1463. c) T. Matsuura, J. W. Bode, Y. Hachisu,
K. Suzuki, Synlett 2003, 1746.
poly-18
aTerephthalohydroxamoly chloride was used as a precursor of bifunctional nitrile
oxide.
Table 3. Molecular weight and thermal properties of poly-
isoxazolines and polyisoxazoles
.
.
.
11 MS 4A have the general formula Na2O Al2O3 xSiO2 yH2O.
12 Polymerization. Both benzene-1,3- and 1,4-dicarbohydroxi-
moyl dichloride were prepared according the literatures.3 A
typical experimental procedure for the reaction of benzene-
1,3-dicarbohydroximoyl dichloride (1) and bisacrylate 4:
To a solution of 1 (50.0 mg, 0.215 mmol) and 6 (46.0 mg,
0.215 mmol) in DMF (0.43 mL) was added non-activated
MS 4A (344 mg) at room temperature. The resulting slurry
was stirred at room temperature for 30 min and at 80 ꢀC for
1 d. The resulting mixture dissolved in CHCl3 was filtrated
and the filtrate was precipitated into MeOH. The precipitates
were filtered, dried in vacuo to give polyisoxazoline poly-5
(84.3 mg, 99% yield) as colorless powder: 1H NMR
(400 MHz, CDCl3): ꢁ 7.76 (brd, 1H), 7.59 (brd, 2H), 7.31
(brd, 1H), 5.13 (brd, 2H), 4.23 (brd, 4H), 3.64 (brd, 4H),
3.56 (brd, 4H); 13C NMR (100 MHz, CDCl3): ꢁ 170.0 (2C),
155.7 (2C), 129.3 (2C), 129.2 (1C), 128.7 (2C), 125.2
(1C), 78.2 (2C), 68.7 (2C), 64.7 (2C), 38.7 (2C); IR (NaCl):
Tg/ꢀC Td5/ꢀC Td10/ꢀC
a
a
a
Entry Products
Mn
Mw
Mw=Mn
1
2
3
4
5
6
7
8
poly-5
poly-6
poly-8
9100 14900
1.6
1.5
1.3
73.6
75.9
57.8
253
266
268
296
241
283
260
279
278
306
269
303
3300
4200
4700b
4400
1500
1200
2200
4900
5400
c
c
c
poly-10
poly-12
poly-14
poly-16
poly-18
—
—
—
145.3
64.3
7000
1900
2400
2800
1.6
1.3
2.0
1.3
c
c
c
—
58.8
—
289
—
336
aEstimated by GPC based on polystyrene standards. bDetermined from the
integral ratio of terminal protons in 1H NMR spectrum. cNot estimated.
benzene (15), and 1,7-octadiyne (17) also proceeded well to
afford polyisoxazoles,12 although the molecular weight was
low, due to the low solubility of the polyisoxazoles which were
precipitated during the polymerization.14
In conclusion, this paper has demonstrated new click chem-
istry utilizing nitrile N-oxide as a 1,3-dipolar molecule coupled
with olefinic and acetylenic compounds, especially from view-
point of macromolecular synthesis. The use of MS 4A to pro-
mote the polycycloaddition is notable for both the mild reaction
conditions and simple procedure and work-up. This protocol of
new click chemistry can be characterized by (i) nonexplosive
materials, (ii) versatility in both 1,3-dipolar molecule and dipo-
larophile, (iii) C–C bond formation, (iv) easy work-up, (v) ab-
sence of catalyst, and (vi) easy transformation of the isoxazoline
and isoxazole moieties, all of which enable access to high-
3062, 2962, 1745, 1261, 1203, 900 cmÀ1
.
13 Structural assignments of polymers were based on the
NOESY correlations. The NOE observed between the
isoxazoline methylene protons or isoxazole methyne protons
and the aromatic proton at the ortho position was diagnostic,
in each case.
14 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Published on the web (Advance View) July 26, 2008; doi:10.1246/cl.2008.918