New ε-caprolactone diyne monomers aiming for biodegradable polymers

Article abstract of DOI:10.1016/j.tetlet.2013.08.080

A substitution reaction of cyclohexane-1,4-diol with propargyl bromide gave 4-(prop-2-yn-1-yloxy)cyclohexanol. This compound was oxidized to the corresponding ketone (2-C₂H) and then to acetylene γ-substituted ε-caprolactone (3-C₂H). The latter compound was chain-extended to two butadiynyl monomers: symmetrical 5,5′-[hexa-2,4- diyne-1,6-diylbis(oxy)]bis(oxepan-2-one) (3-C₄-3) and unsymmetrical 5-{[5-(trimethylsilyl)penta-2,4-diyn-1-yl]oxy}oxepan-2-one (3-C₄TMS) via Eglinton and Cadiot-Chodkiewicz couplings, respectively. Both compounds were obtained through an alternative Baeyer-Villiger oxidation of immediate ketone precursors 2-C₄-2 and 2-C₄TMS.

Full text of DOI:10.1016/j.tetlet.2013.08.080

Tetrahedron Letters 54 (2013) 6032–6034
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New
e
-caprolactone diyne monomers aiming for biodegradable
polymers
⇑
Bartłomiej Pigulski, Nurbey Gulia, Sławomir Szafert
Department of Chemistry, University of Wrocław, 14 F. Joliot-Curie, 50-383 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A
substitution reaction of cyclohexane-1,4-diol with propargyl bromide gave 4-(prop-2-yn-1-
yloxy)cyclohexanol. This compound was oxidized to the corresponding ketone (2-C2H) and then to acet-
ylene -substituted -caprolactone (3-C2H). The latter compound was chain-extended to two butadiynyl
Received 15 June 2013
Revised 5 August 2013
Accepted 21 August 2013
Available online 5 September 2013
c
e
monomers: symmetrical 5,50-[hexa-2,4-diyne-1,6-diylbis(oxy)]bis(oxepan-2-one) (3-C4-3) and unsym-
metrical 5-{[5-(trimethylsilyl)penta-2,4-diyn-1-yl]oxy}oxepan-2-one (3-C4TMS) via Eglinton and Cadi-
ot–Chodkiewicz couplings, respectively. Both compounds were obtained through an alternative
Baeyer–Villiger oxidation of immediate ketone precursors 2-C4-2 and 2-C4TMS.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
e-Caprolactone
Polyynes
ROP
Cadiot–Chodkiewcz coupling
Eglinton coupling
Lactones including
e
-caprolactones (
e
-CL) are of interest to the
ing monomer can also be transformed into an oligoyne via a
chain-elongation reaction (e.g., Cadiot–Chodkiewicz14 or Negishi
cross-coupling15). Polymerization of such monomers would result
in an aliphatic polyester with an unsaturated sp carbon chain,
which are compounds known to possess interesting physical prop-
erties such as nonlinear optical responses (NLOs) or large molecu-
lar first and second-order hyperpolarizabilities.16
scientific community due to their use as precursors of useful biode-
gradable polymers—the aliphatic polyesters.1 Using a controlled
ring-opening polymerization (ROP), e-caprolactones can easily be
transformed into highly defined polymers with low mass disper-
sion, holding variable and further processable end-groups.2 Such
polymers are, for instance, used in the packaging industry as alter-
native materials for traditional non-biodegradable polymers such
as polyethylene.3 They are also used in medicine as stents, artificial
implants, or drug delivery systems.4
In order to improve their physical properties (especially the
glass transition temperature) many
were designed and prepared. The literature describes monomers
with halogen,5 azide,6 ketone,7 hydroxyl,8 or amine9 groups on
the lactone ring. Also unsaturated precursors with a double bond10
within the macrocycle are known. Surprisingly, among the many
Accordingly, the initial goal of this project was to prepare an
e-
caprolactone monomer containing an ethynyl group at the -posi-
c
tion of the ring as shown in Scheme 1. The Br-substituted (1-Br)
precursor for the target 1-C2TMS was synthesized from 7-oxabicy-
clo[2.2.1]heptane, which, using HBr, was first transformed into 4-
bromocyclohexanol,17 and then consecutively oxidized first to
e-caprolactone derivatives
the ketone and then to
c-bromo-e-caprolactone using the Bae-
yer–Villiger protocol, as described in the literature.5a
With 1-Br in hand, several approaches have been attempted to
prepare 1-C2TMS as summarized in Table 1. The first attempt was a
simple substitution of bromine by trimethylsilylacetylene. Numer-
ous catalytic systems as well as different reaction conditions were
tested and some of the results are presented in Table 1. For exam-
ple, the known sp–sp3 Sonogashira-type heterocouplings18 (entries
1–3) did not work, even with the use of the carbyne PEPPSI-IPr
functional groups, acetylenic derivatives of
not yet been synthesized. To the best of our knowledge, only a
e-caprolactone have
copolymer of e-caprolactone with acetylene-functionalized d-val-
erolactone is currently known.11
The acetylene functional group has many advantages. The ethy-
nyl group can be first polymerized to polyacetylene12 and then the
lactone group may undergo ROP yielding hyperbranched polymers.
e
-Caprolactone with an acetylenic moiety may also be easily func-
O
O
TMSC CH
catalyst
tionalized by copper-catalyzed cycloaddition with azides (‘click
TMS
Br
chemistry’) yielding substituted triazoles.13 An acetylene-contain-
O
O
1-Br
1-C2TMS
⇑
Corresponding author. Tel.: +48 71 375 7122; fax: +48 71 238 2348.
E-mail address: slawomir.szafert@chem.uni.wroc.pl (S. Szafert).
Scheme 1. Attempted synthesis of C2TMS substituted
e
-caprolactone.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.080

B. Pigulski et al. / Tetrahedron Letters 54 (2013) 6032–6034
6033
Table 1
Conditions tested for
c-ethynyl-
e
-caprolactone synthesis from
Catalytic system
c-bromo-e-caprolactone
Entry
Solvent
Acetylene
1a
2a
3a
4a
5
Pd(PPh3)2Cl2 (2.5%), CuI (5%)/K2CO3 (2 equiv)
Pd(PPh3)2Cl2 (5%), CuI (10%)/Et3N
PEPPSI-IPr (2%), CuI (8%)/Cs2CO3 (1.4 equiv)
Co(acac)3 (0.4 equiv)
DMF
Et3N
DMF/DME
THF
THF
TMSC„CH (1.5 equiv)
TMSC„CH (1.5 equiv)
TMSC„CH (1.5 equiv)
HC„CMgBr (4 equiv)
(TMSC„C)2CuLi
—
a
Degradation of the starting material was observed.
OH
OH
OH
O
O
O
embed a linkage that would allow us to safely attach an ethynyl
group to the lactone ring.
As shown in Scheme 2, the synthesis was started from a mixture
of trans- and cis-cyclohexane-1,4-diol. Initially, 4-(propargyloxy)-
cyclohexanone (2-C2H) was obtained by reaction with propargyl
bromide in the presence of sodium hydride.
Br
NaH, DMF
PCC, CH2Cl2
RT, 24 h
0 °C to RT
24 h
15% (2-C2H)
This step was not selective and a mixture of the substrate
and mono and disubstituted products was obtained. The sub-
strate could easily be removed by diethyl ether extraction,
but some difficulties were encountered with separation of the
product from the disubstituted side-product. After several
unsuccessful trials, the mixture of both products was oxidized
with PCC and the monoacetylene substituted ketone (2-C2H)
was isolated by silica gel chromatography with dichlorometh-
ane/ethyl acetate (v/v, 20/1) as the eluent to give 4-(propargyl-
oxy)cyclohexanone as a yellow oil in 15% yield. Finally, 5-(prop-
2-yn-1-yloxy)oxepan-2-one (3-C2H) was obtained as a yellow
solid in 94% yield from 2-C2H through the Baeyer–Villiger
oxidation as shown in Scheme 3.
Scheme 2. Synthesis of 2-C2H.
catalyst.19 Additionally, degradation of the starting material was
observed. In the next attempt, we investigated cobalt-catalyzed
coupling with a Grignard reagent20 (entry 4), which also did not
give the desired product. Similarly, 1-Br did not undergo reaction
with the Gilman reagent (entry 5).
Since in most cases we observed degradation of the starting
material, confirming that the e-caprolactone ring was quite sensi-
tive, we decided to carry out the Sonogashira coupling between
acetylene and 4-bromocyclohexanone or 4-bromocyclohexanol
(e-caprolactone precursors; see Scheme 1), and then oxidize the
acetylene-substituted product to the desired lactone. Unfortu-
nately these reactions also did not give the product.
Struggling to form a C–C bond between the acetylene sp carbon
and the alkyl sp3 carbon from the lactone ring, we decided to
Both 2-C2H and 3-C2H were excellent substrates/precursors for
further development of new e-caprolactone monomers. The ulti-
mate targets at this stage were diynes 3-C4TMS and 3-C4-3, for
which two alternative pathways were investigated. In the first
method (A), both compounds were obtained from 3-C2H by
B
O
O
O
O
mCPBA, CH2Cl2
O
O
RT, 5 d, 54%
O
O
O
O
(2-C4-2)
(3-C4-3)
A
B
Cu(AcO)2, pyridine
55 °C,3 h, 44%
Cu(AcO)2,pyridine
55 oC, 3 h, 76%
O
O
O
A
O
mCPBA,CH2Cl2
RT, 24 h, 94%
O
(2-C2H)
(3-C2H)
A
B
BrC2TMS,CuI, NHiPr2
Pd(PPh3)2Cl2
BrC2TMS, CuI, NHiPr2
Pd(PPh3)2Cl2
THF,RT, 24 h, 29%
THF, RT, 24 h, 21%
B
mCPBA,CH2Cl2
O
Si
Si
RT, 24 h, 21%
O
O
O
O
(2-C4TMS)
(3-C4TMS)
Scheme 3. Synthesis of oligoynic derivatives of
e-caprolactone.

6034
B. Pigulski et al. / Tetrahedron Letters 54 (2013) 6032–6034
oxidative homocoupling (3-C4-3, 76%) and by Cadiot–Chodkiewicz
cross-coupling with BrC„CTMS (3-C4TMS, 21%).
In method (B), e-caprolactone precursor 2-C2H was first homo-
coupled to give 2-C4-2 (44%) or elongated to afford 2-C4TMS via the
be precursors for longer polyynic derivatives and polyyne-contain-
ing biodegradable polymers. All new compounds were character-
ized by spectroscopic methods and may be potentially used as
monomers for new biodegradable polymers with unsaturated, oli-
goynic fragments.
Cadiot–Chodkiewicz protocol (29%), and then both compounds
were oxidized to the respective e-caprolactones in 54% (3-C4-3)
and 21% (3-C4TMS) yields. In both methods Pd(PPh3)2Cl2/CuI21
was used as the catalytic system for the chain-elongation and
Cu(AcO)2 in pyridine (Eglinton homocoupling) was used for the
terminal acetylene dimerization.22
Acknowledgments
The authors would like to thank the National Science Center
(Grant N204 136339) for support of this research.
The reaction yields were much higher for method A, that is after
the Baeyer–Villiger reaction was performed on the monomer
2-C2H, it was applied to oligoynic ketones (the overall yields for
3-C4TMS were A: 20%, B: 6%; and for 3-C4-3: A: 71%, B: 24%). Addi-
tionally the Baeyer–Villiger oxidation of 2-C4TMS and 2-C4-2
required longer reaction times (4 and 5 days, respectively). Hence,
this pathway was used for larger scale syntheses.
Supplementary data
Supplementary data (Synthetic procedures, materials and
methods, spectroscopic data and copies of 1H and 13C NMR spectra
for all new compounds.) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2013.08.080.
All the new compounds were characterized by 1H and 13C NMR
spectroscopy (see Supplementary data) and gave correct microa-
nalyses and/or high-resolution mass spectra. The NMR signals
were assigned based on COSY, HMQC, and HMBC experiments. In
the proton spectrum of 2-C2H a diagnostic signal due to the triplet
for the terminal acetylene proton at d 2.44 and a doublet for the
propargyl CH2 group at d 4.24 indicated efficient substitution of
bromine for a propargyl group. There were also four multiplets
due to the diastereotopic protons of the CH2 groups and a multil-
plet for the CH group observed for 2-C2H.
References and notes
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d 87.6
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