Hydroxyapatite-supported palladium-catalyzed efficient synthesis of (E)-2-alkene-4-ynecarboxylic esters. Intense fluorescene emission of selected compounds

Article abstract of DOI:10.1021/jo800209z

(Chemical Equation Presented) A simple procedure for the synthesis of substituted (E)-2-alkene-4-ynecarboxylic esters has been achieved using hydroxyapatite-supported palladium as efficient catalyst surface. The catalyst is recycled, and the turnover number (TON) based on Pd is 16000. A naphthyl-substituted derivative gives very intense fluorescence emission.

Full text of DOI:10.1021/jo800209z

SCHEME 1. Coupling of Diiodoalkenes and Conjugated
Alkenes
Hydroxyapatite-Supported Palladium-Catalyzed
Efficient Synthesis of
(E)-2-Alkene-4-ynecarboxylic Esters. Intense
Fluorescene Emission of Selected Compounds
Brindaban C. Ranu,* Laksmikanta Adak, and
Kalicharan Chattopadhyay
Department of Organic Chemistry, Indian Association for the
CultiVation of Science, JadaVpur, Kolkata - 700 032, India
here a facile synthesis of (E)-2-alkene-4-ynoate system by the
coupling of Vicinal-diiodoalkenes with conjugated carboxylic
esters catalyzed by nonstoichiometric PdHAP (Scheme 1). The
TEM image of our fresh and used nonstoichiometric PdHAP
catalyst did not show discrete particles (see the Supporting
Information) corresponding to Pd(0).3c
ocbcr@iacs.res.in
ReceiVed January 27, 2008
The stereodefined 2-en-4-ynoate moiety or its derivatives are
of considerable interest in organic synthesis because of their
presence in many natural products of promising biological
activities5 and their potential as advanced materials for electronic
and photonic applications.6 This unit is usually synthesized by
homogeneous Pd- or Pd/Cu- or Cu-catalyzed coupling of alkyne
or an organometallic alkyne and a vinyl halide.7–9 Recently,
we reported a Pd nanoparticle-catalyzed coupling of Vic-
diiodoalkenes and conjugated alkenes to build up this unit.10
However, none of these methods7–9 including ours10 offered
satisfactory catalytic recyclability and large turnover number
(TON). To accommodate these two prime criteria for industrial
applications, we considered a heterogeneous HAP-based catalyst
for this important reaction.
The experimental procedure is very simple. A stirred mixture
of Vic-diiodoalkene, acrylic ester in N-methylpyrrolidone (NMP)
was heated at 90-100 °C in the presence of PdHAP and K2CO3
for a certain period of time (TLC). Standard workup provided
the product. The catalyst, PdHAP, was recycled up to three times
without appreciable loss of efficiency (see the Experimental
Procedure and Table 5).
A simple procedure for the synthesis of substituted (E)-2-
alkene-4-ynecarboxylic esters has been achieved using hy-
droxyapatite-supported palladium as efficient catalyst surface.
The catalyst is recycled, and the turnover number (TON)
based on Pd is 16000. A naphthyl-substituted derivative gives
very intense fluorescence emission.
Catalysis by palladium anchored on a heterogeneous support
for carbon-carbon coupling has received tremendous attention
in recent times.1 The main advantages of heterogeneous catalysts
compared to their homogeneous counterparts are ease of
separation, reusability, improved efficiency due to stable active
site and better steric control of a reaction intermediate.2 These
qualities of heterogeneous catalysts made them very promising
for applications in industry.
Several substituted Vic-diiodoalkenes underwent coupling with
acrylic esters under the catalysis of PdHAP by this procedure
to produce the corresponding enynecarboxylic esters in high
yields. The results are summarized in Table 3.
Hydroxyapatite, a Ca-phosphate complex, is found to be one
of the best active heterogeneous supports cabable of accom-
modating a variety of metals and metal salts.3 One of these
hydroxyapatite-supported palladium complexes, nonstoichio-
metric PdHAP containing Pd2+, has been used very successfully
for the Heck and Suzuki coupling reactions.4 We now report
Both aryl- and alkyl-substituted diiodoalkenes participated
in this reaction. The coupling is stereoselective, giving (E)-esters
in all reactions. The Br, Cl, and F substituents on the aromatic
ring (entries 5-9, Table 3) of the aryl group did not interfere
in the coupling with diiodoalkenes. The corresponding Vic-
dibromoalkenes (entry 17, Table 3) also coupled with acrylic
(1) Yin, L.; Leibescher, J. Chem. ReV. 2007, 107, 133–173.
(2) (a) Gates, B. C. Chem. ReV. 1995, 95, 511–522. (b) Bergbreiter, D. E.
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T.; Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2004, 126, 10657–10666. (d)
Hara, T.; Mori, K.; Oshiba, M.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Green
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10.1021/jo800209z CCC: $40.75
Published on Web 06/18/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5609–5612 5609

TABLE 1. Standardization of Catalyst System
TABLE 3. Coupling of Diiodoalkenes with Activated Alkenes
palladium
loadings
time yield
entry
catalyst system
(mol%)
(h)
(%)
TON
1a
2
3
4
5
PdCl2, TBAB, Na2CO3
stoichiometric PdHAP
2.0
7.0
10.0
6.0
10.0
10.0
10.0
10.0
78
15
75
39
2500
16666
6 × 10-3
nonstoichiometric PdHAP 4.5 × 10-3
PdCl2(PhCN)2
Pd/C (10%)
Pd/CuO (5%)
Pd/ZnO (5%)
2.0
0.37
0.47
0.47
55
50
40
148
107
86
6
7
a The reaction in entry 1 was carried out in H2O.
TABLE 2. Standardization of Solvent
entry
solvent
T (°C)
time (h)
yield (%)
1
2
3
4
5
6
H2O
THF
toluene
DMF
NMP
CH3CN
90
70
90
90
90
75
8.0
8.0
8.0
8.0
6.0
8.0
35
60
75
esters; however, the reaction time was longer and yield was
lower compared to diiodo counterparts.
To explore potential of these enynecarboxylic esters for useful
applications, the absorption and fluorescence properties of these
compounds were studied.12 The five compounds showed very
promising absorption and fluorescence, as highlighted in Table
4, Figure 1, and Figure 2.
To determine the most suitable catalyst, a variety of hetero-
geneous Pd catalysts as shown in Table 1 were investigated.
As evident from the results, nonstoichiometric PdHAP was
found to be the best one with a TON of 16666.11 Similarly, a
study of solvent system (Table 2) compatible with PdHAP
showed NMP as the most effective.
a
1
Yields refer to those of purified products characterized by IR and H
and 13C NMR spectroscopic data. b This substrate is a dibromoalkene.
However, except for alkyl-substituted enyne esters, all
products showed considerable emission. In general, increased
conjugation in the system leads to increasing red shift in
emissionspectrum.ThiscanbeexplainedbylowerFranck-Cordon
energy gap due to increased delocalization of the π network.6
Among these five fluorescent enyne esters, the naphthyl deriva-
tive (entry 1, Table 4) was found to be the best showing a λmax
at 333 nm (Figure 1) and λem 443 nm (methanol) (Figure 2). A
solvent study with regard to emission was done with the
naphthyl derivative, and it was found that it showed lesser λem
in nonpolar solvent like cyclohexane compared to that in highly
polar methanol solvent (Figure 3). This indicated that the
emissive state of naphthyl derivative is strongly dependent on
TABLE 4. Absorption and Emission Data of Enyne Compounds in
Methanol
(12) (a) Abreu, A. S.; Ferreira, P. M. T.; Queiroz, M.-J.R.P.; Gatto, E.;
Venanzi, M. Eur. J. Org. Chem. 2004, 3985–3991. (b) Abreu, A. S.; Silva, N. O.;
Ferreira, P. M. T.; Queiroz, M.-J.R.P.; Venanzi, M. Eur. J. Org. Chem. 2003,
4792–4796. (c) Nikano, Y.; Ishizuka, K.; Muroka, K.; Ohtani, H.; Takayama,
Y.; Sato, F. Org. Lett. 2004, 6, 2373–2376.
solvent. The intense fluorescence of the naphthyl derivative may
be attributed to the structural rigidity of naphthalene moiety
which significantly reduces the nonradiative mechanism leading
to high quantum yield, 0.22 (determined using a fluorescent
probe, coumarin 480, C 480, exciton in cyclohexane with a
(11) Lower yield of product and TON with the use of stoichiometric PdHAP
(entry 2, Table 1) compared to nonstoichiometric PdHAP (entry 3, Table 1) is
probably due to the relatively less efficiency of stoichiometric PdHAP in coupling
reactions as this catalyst surface has a lower concentration of phosphate anions,
which are necessary to statibilize the resulting higher oxidation state of
palladium.4.
5610 J. Org. Chem. Vol. 73, No. 14, 2008

SCHEME 2. Synthesis of Peptide
FIGURE 1. Absoption spectra of five selected enynes designated by
their entries in Table 4.
SCHEME 3. Possible Reaction Pathway
It may be predicted that this PdHAP-catalyzed coupling does
not proceed via the traditional Pd0/PdII cycle as no Pd(0) was
detected in the fresh and used catalyst, and it is more likely
that it goes via the PdII/PdIV state, as reported in other PdHAP-
catalyzed Heck reactions.4 Two alternative routes were consid-
ered for this reaction (Scheme 3). In route a, the diiodoalkene
on treatment with PdHAP under the reaction conditions produces
the iodoalkyne which then couples with acrylic ester to provide
the product. The intermediate iodoalkyne isolated as the sole
product in a separate experiment using PdHAP, produced the
en-yne carboxylic ester on reaction with n-butyl acrylate. Thus,
route a is obviously the most probable path. Route b demon-
strates initial Heck coupling followed by HI elimination to give
the product. The selective Heck coupling with terminal iodide
group at the first step may be rationalized by steric reasons and
the subsequent preferential HI elimination over further Heck
coupling was supported by a model experiment with iododiphe-
nylethylene, as outlined in Scheme 3. Hence, operation of route
b is also not ruled out.
In conclusion, we have developed a convenient and efficient
procedure for the synthesis of (E)-2-alkene-4-ynecarboxylic
esters by a simple reaction of Vic-diiodoalkenes with acrylic
esters catalyzed by hydroxyapatite-supported palladium com-
plex. In addition to excellent stereoselectivity, good yields of
products and simple operation, the most attractive features of
this methodology are recylability of catalyst and high turnover
number (>16000). Fluorescence properties of the enyne esters
indicate the possible application of this type of compounds as
fluorescent markers. One of these compounds showed remark-
able fluorescence with very high quantum yield and is endowed
with potential to be used as a biomarker.
FIGURE 2. Emisssion spectra of five selected enynes.
FIGURE 3. Comparison of emission of the naphthyl derivative in
different solvents ((1) cyclohexane; (2) CCl4; (3) CH3CN; (4) methanol).
reported quantum yield of 1.05).13 Certainly, these enyne esters,
particularly the naphthalene derivative with excellent fluores-
cence emission, may be considered as a good biomarker through
tagging with a biologically active unit. To check the feasibility
of this hypothesis, the (E)-5-naphthalene-1-ylpent-2-en-4-ynoic
acid butyl ester 1 was hydrolyzed to give the corresponding
acid 2 which was coupled with a tryptophan moiety to give the
corresponding peptide 3 (Scheme 2). This class of compounds
might have promising biological activities.14 A systematic and
detailed investigation to find the useful applications of a series
of these peptides will constitute our next endeavor.
(13) Jones, G., II; Jackson, W. R.; Choi, C.-y. J. Phys. Chem. 1985, 89,
294–300.
Experimental Section
(14) (a) Palermo, J. A.; Flower, P. B.; Seldes, A. M. Tetrahedron Lett. 1992,
33, 3097–3100. (b) Tse, F. L. S.; Christiano, J. R.; Talbot, K.C., J. Pharm.
Pharmacol. 1984, 36, 633–636. (c) Wissner, P.; Dahse, H.-M.; Schlitzer, M.
Pharmazie 2001, 56, 33–35.
General Experimental Procedure for the Synthesis of Enyne
Esters. Representative Procedure for 5-Phenylpent-2-en-4-
J. Org. Chem. Vol. 73, No. 14, 2008 5611

TABLE 5. Recyclability of the Catalyst
Many of these products are known compounds and were easily
identified by comparison of their spectroscopic data with those
reported (see references in Table 3). The unknown compounds were
cycle no.
time (h)
yield (%)
TOF (h-1
)
1
2
3
4
6
6
8
75
72
60
20
2778
2667
1667
370
1
properly characterized by their spectroscopic data (IR, H NMR,
13C NMR, HRMS). The purity of all compounds was also checked
1
by H NMR, 13C NMR, and HRMS.
12
Acknowledgment. This investigation has enjoyed the finan-
cial support of DST, New Delhi, by a grant [SR/S5/GC-02/
2006]. L.A. and K.C. are thankful to CSIR for their fellowship.
We also thank Professor Kankan Bhattacharyya of the depart-
ment of Physical Chemistry, IACS, for his help with the
fluorescence studies.
ynoic Acid Butyl Ester (Entry 1, Table 3). To a stirred mixture
of 1,2-diiodovinylbenzene (3.56 g, 10 mmol) and butyl acrylate
(3.84 g, 30 mmol) in N-methylpyrrolidone (NMP, 12 mL) were
added PdHAP (30 mg, 0.00045 mmol of Pd) and potassium
carbonate (3.5 g, 25 mmol). The mixture was then heated at
90-100 °C (oil bath) for 6 h (TLC). After being cooled, the reaction
mixture was extracted with Et2O (5 × 10 mL). The ether extract
was washed with water and brine and dried (Na2SO4). Evaporation
of solvent left the crude product which was purified by column
chromatography over silica gel (ether-hexane 5:95) to afford the
pure product (1.7 g, 75%) 5-phenyl-1-pent-2-en-4-ynoic acid butyl
Supporting Information Available: Characterization data
1
(IR, H and 13C NMR, and HRMS spectroscopic data) of the
products in entries 2, 4, 6-9, 11, 14, and 15, Table 3. Copies
1
of H and 13C NMR spectra of all products listed in Table 3.
ester as a yellow oil. The spectroscopic data (IR, 1H NMR and 13
C
This material is available free of charge via the Internet at
http://pubs.acs.org.
NMR) are in good agreement with the reported values.10 The
remaining catalyst, PdHAP, was reused for three subsequent
reactions without much loss of efficiency (Table 5).
JO800209Z
5612 J. Org. Chem. Vol. 73, No. 14, 2008