Palladium-catalyzed annulation of internal alkynes in aqueous medium

Article abstract of DOI:10.1039/c3ra46010j

To facilitate precatalyst recovery and reuse, we have developed a fluorous, oxime-based palladacycle 1 and demonstrated that it is a very efficient and versatile precatalyst for carbo- and heteroannulation of internal alkynes with functionalized aryl halides in aqueous medium. A uniform reaction condition for these annulation reactions was also developed.

Full text of DOI:10.1039/c3ra46010j

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Palladium-catalyzed annulation of internal alkynes
in aqueous medium†
Cite this: RSC Adv., 2014, 4, 4921
a
b
b
a
*
*
Wei Jie Ang, Chih-Hsuan Tai, Lee-Chiang Lo and Yulin Lam
Received 22nd October 2013
Accepted 2nd December 2013
To facilitate precatalyst recovery and reuse, we have developed a fluorous, oxime-based palladacycle 1 and
demonstrated that it is a very efficient and versatile precatalyst for carbo- and heteroannulation of internal
alkynes with functionalized aryl halides in aqueous medium. A uniform reaction condition for these
annulation reactions was also developed.
DOI: 10.1039/c3ra46010j
www.rsc.org/advances
its application as a precatalyst in a wide variety of C–C
coupling reactions in aqueous and organic media under
microwave irradiation.13 As palladacycle 1 is a “light uo-
rous” compound, it can be easily recovered using reusable
uorous silica gel14 eluted with common organic solvents.
This avoids the use of peruorinated solvent which is
persistent in the environment.15 The lower toxicity and
persistence of “light uorous” compounds thus make it
comparably more environmentally friendly than its “heavy
uorous” counterpart.
Analysis of the homogeneous and heterogeneous palladium-
catalyzed carbo- and heteroannulation of internal alkynes with
functionalized aryl halides (Fig. 1) revealed that they were highly
dependent on the choice of solvent, base, and additives.9,11a,b
Herein we investigate the possibility of developing a uniform
reaction condition suitable for all these annulation reactions.
More importantly, we explore the application of palladacycle 1
as a recyclable precatalyst for carbo- and heteroannulation
reactions in aqueous medium.
Introduction
Annulation of internal alkynes with functionalized aryl
halides is a versatile and useful method for the synthesis of a
wide variety of carbo- and heterocycles (Fig. 1).1–8 To date,
many homogeneous transition metal-based catalytic systems
have been developed for this transformation.9 Although
homogeneous catalysis have many advantages, difficulties in
separation and recovery of the catalyst and product contam-
ination with traces of the heavy metal are common problems
encountered which restrict their applications in the indus-
tries.10 To circumvent this problem, various annulation
strategies involving heterogeneous catalysis have been devel-
oped.11 Heterogeneous catalysts can be separated from the
reaction mixture in a straightforward manner, such as by
ltration, but on the other hand, diffusion of the reactants to
the solid catalyst occurs less readily, thus affecting the reac-
tion rate.
An alternative strategy is uorous catalysis which
combines the advantages of homogenous catalysis for reac-
tivity and heterogeneous catalysis for catalyst recovery.12 Since
12b
´
´
the seminal work by Horvath and Rabai,
a selection of
uorous ligands and catalysts have been developed for the
catalysis of a variety of reactions. However to the best of our
knowledge, there are no previous reports on the uorous
catalysis of carbo- and heteroannulation of internal alkynes
with functionalized aryl halides. Previously, we reported the
synthesis of a chemically and thermally stable uorous,
oxime-based palladacycle
1 (Fig. 2) and demonstrated
aDepartment of Chemistry, National University of Singapore, 3 Science Drive 3,
Singapore 117543. E-mail: chmlamyl@nus.edu.sg; Fax: +65-67791691; Tel: +65-
65162688
bDepartment of Chemistry, National Taiwan University, No. 1, Sec. 4 Roosevelt Road,
Taipei 106, Taiwan. E-mail: lclo@ntu.edu.tw; Fax: +886-233668670; Tel: +886-
233661669
† Electronic supplementary information (ESI) available: Spectral data for
compounds 3a–d, 3d0, 5a–d, 5d0, 7a–e, 9a–m, 11a–e, 11e0, 13a–e, and 15a–g are
included in the ESI. See DOI: 10.1039/c3ra46010j
Fig. 1 Typical Pd-catalyzed annulation of functionalized aryl halides
with internal alkynes.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 4921–4929 | 4921

View Article Online
RSC Advances
Paper
Table 2 Effect of alkyne stoichiometry on annulationa
Entry
1c
Aryl halide
Alkyne (equiv.)
Product
Yieldb (%)
59
Fig. 2 Structure of palladacycle 1.
2c
3c
(3)
(5)
65
65
Results and discussion
Carboannulation of aromatic carbonyl compounds with
4d
(1.5)
75
internal alkynes
5d
6d
(3)
(5)
80
80
Initial assessment of the annulation reaction was conducted
using 2-bromobenzaldehyde 2a and diphenylacetylene with
palladacycle 1 as precatalyst (1 mol% Pd), K2CO3 as base, DMF
as solvent and tetra-n-butylammonium bromide (TBAB) as an
additive under conventional heating at 130 ꢀC. The desired
indenone 3a was obtained aer 1.5 h in 92% yield (Table 1,
entry 1). To facilitate an expedient synthesis of 3a, we eꢀxplored
the same reaction under microwave irradiation at 150 C. The
reaction was completed in 25 min and gave indenone 3a in 98%
yield (Table 1, entry 2). To develop a more environmentally
friendly condition for this synthesis, we examined using water
as a reaction solvent. However, when DMF was replaced with
water, the yield of compound 3a decreased to 57% (Table 1,
entry 3). To optimize the reaction, we rst varied the base and
found that the reaction in aqueous medium proceeded most
efficiently with Na2CO3 (Table 1, entries 4–11). Next, we inves-
tigated the effect of temperature on the reaction. The results
indicated that although the reaction completed more rapidly at
7e
(1.5)
60
8e
9e
(3)
(5)
62
63
a
Reaction conditions: aryl halide (1 equiv.), alkyne (see Table 2),
palladacycle 1 (1 mol %), TBAB (1 equiv.), Na2CO3 (2 equiv.) and H2O
b
c
d
(0.25 M). Isolated yields. M.W. at 150 ꢀC for 20 min. M.W. at
150 ꢀC for 30 min. e M.W. at 150 ꢀC for 27 min.
a higher temperature, compound 3a was obtained in lower
yields when the reaction temperature was increased to 160 ꢀC or
lowered to 140 C (Table 1, entries 12–13). We also examined
the effect of the loading of palladacycle 1 on the reaction. When
the amount of palladacycle 1 was lowered (0.5 mol% Pd), the
reaction required a longer time to complete and compound 3a
ꢀ
Table 1 Optimization of the palladium-catalyzed carboannulation was obtained in a lower yield (Table 1, entry 14). Finally
reaction between 2-bromobenzaldehyde and diphenylacetylenea
replacement of TBAB with LiCl did not provide any improve-
ment in the reaction either and Pd black was observed to form
during the reaction (Table 1, entry 15).
Larock et al.4 have reported earlier that the volatility of liquid
alkynes could have an effect on the reaction rate and product
yield. Thus, we have also investigated the effect of the stoichi-
ometry of liquid alkyne on the reaction (Table 2). Using the
Entry Base
Solvent Temp. (ꢀC) Time (min) Yield of 3ab (%)
optimized reaction conditions, various aryl halides were used to
determine the optimal concentration of alkyne. When 1 equiv-
alent of alkyne was employed, the reaction was incomplete
(based on TLC analysis). It required 1.5 equivalents of alkyne for
the reaction to proceed to completion. Increasing the amount of
alkyne to 3 equivalents resulted in a higher yield of the
respective desired product (Table 2, entries 2, 5 and 8). However
further increasing the amount of alkyne to 5 equivalents did not
provide any improvement in yields (Table 2, entries 3, 6 and 9).
To demonstrate the generality of this reaction condition for
the synthesis of 2,3-disubstituted-1-indenones 3, we applied it
on various substrates (Table 3). Besides 2a, o-iodo or o-chlor-
obenzaldehyde and o-bromobenzonitrile can also be employed
successfully to the carboannulation reaction, with the iodide
showing the highest reactivity. In addition, palladacycle 1 gave
comparable yield of indenone 3 as compared to its non-uorous
analog and higher yields as compared to other Pd catalysts.
1c
2
3
4
5
6
7
8
9
10
11
12
13
14d
15e
K2CO3
DMF
DMF
H2O
H2O
H2O
H2O
130
150
150
150
150
150
150
150
150
170
150
160
140
150
150
90
25
120
40
20
35
120
120
35
10
30
92
98
57
52
68
9
K2CO3
K2CO3
KOtBu
KOAc
KOH
NH4OAc H2O
TEA
NaOAc
NaOAc
Na2CO3 H2O
Na2CO3 H2O
Na2CO3 H2O
Na2CO3 H2O
Na2CO3 H2O
0
0
H2O
H2O
H2O
72
71
96
82
92
88
85
15
50
50
25
a
1
equivalent of 2a (0.25 mmol) and 1.5 equivalent of
b c d
diphenylacetylene.
Isolated yields. Conventional heating.
0.5
mol% Pd. e LiCl used instead of TBAB.
4922 | RSC Adv., 2014, 4, 4921–4929
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Table 3 Synthesis of 2,3-disubstituted-1-indenones using palladacycle 1
Alkyne
Alkyne
R1
Product(s)
Entry
1
2
R1
R2
Time (min)
Product(s) (yielda) Entry
2
R2
Time (min) (yielda)
Ph
Ph
30 (2b h, 36c h, 30d)
7i
n-Pr
n-Pr 18 (3e h)
2
3
4
5
SiMe3 Ph
23
8
Ph
Ph
Ph
Me
Ph
Ph
15 (1.5e,h h)
n-Pr
n-Pr 25
9i
60 (6b h)
Ph
Me
22 (1e,f h)
10
11
23
15
Ph
Ph
20 (13c h)
12 (17e h)
SiMe3 Ph
6
SiMe3 Ph
a
c
Isolated yields. b Using 4,40-dichlorobenzophenone oxime palladacycle: 1 mol% Pd, K2CO3, TBAB, DMF, 130/160 ꢀC.9g Using Pd(OAc)2: 5 mol%
Pd, NaOAc, TBAC, DMF, 100 ꢀC.1 Using 4,40-dimethoxybenzophenone oxime palladacycle: 1 mol% Pd, Na2CO3, TBAB, H2O, M.W. 150 ꢀC. e Using
d
Pd(OAc)2: 5 mol% Pd, Na2CO3, TBAC, DMA, 100 ꢀC.1 Reaction provides a 1 : 1 mixture of regioisomers 3d and 3d0 in 56% total yield. g In addition to
f
h
compound 3c, the isomerized product, b,g-enone was formed in ꢁ1 : 1 ratio.1 Reaction provides a 1 : 1 mixture of regioisomers 3d and 3d0 in 62%
total yield. i 170 ꢀC.
Earlier studies have shown that isomerization to b,g-enones is a (Table 3, entries 3 and 7). It is also worth noting that the car-
frequent problem during the synthesis of indenones bearing a boannulation process using palladacycle 1 is regiospecic for
primary alkyl group in the 3-position.1 However it is gratifying to alkynes containing a hindered group such as a trimethylsilyl
note that carboannulation with palladacycle 1 provided solely group, yielding only the isomer with the hindered group on the
the a,b-enones, and the b,g-enone isomer was not observed 2-position (Table 3, entries 2 and 6). This is an improvement
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 4921–4929 | 4923

View Article Online
RSC Advances
Paper
over the carboannulation process with Pd(OAc)2 where the discrepancy (Table 4, entry 2). On the other hand, the reac-
reaction is regioselective and indenone 3b is obtained as a tion of 4a with 1-phenyl-1-propyne was less regioselective and
major product.1 However, when the steric hindrance between provided a mixture of regioisomers in 2 : 1 ratio (Table 4,
the two ends of the triple bond becomes less apparent as in the entry 4). 2-Iodoacetophenone 4b also underwent the same
case of 1-phenyl-1-propyne, palladacycle 1, like Pd(OAc)2, reaction but afforded the indenols in lower yields (Table 4,
produces an approximate 1 : 1 ratio of the regioisomers entries 5 and 6), which is consistent with previously reported
(Table 3, entries 4 and 8).
results.2
Encouraged by these results, we extended our studies to
the carboannulation of aromatic ketones 4 which gave 2,3-
Carboannulation of nitriles with internal alkynes
disubstituted-1-indenol
(Table 4). Excellent regioselectivity was similarly observed
when 4a was reacted with alkynes carrying a larger steric
5
in good to moderate yields
Next, we explored applying palladacycle 1 to the synthesis of
3,4-disubstituted-2-naphthylamines by using 2-(2-iodophenyl)
acetonitrile 6 as the substrate (Table 5). Comparison of palla-
dacycle 1 with the Pd(OAc)2 catalyst showed that the car-
boannulation reaction with palladacycle 1 gave a higher yield
of the product and occurred in a regiospecic manner with the
more hindered substituent of the unsymmetrical alkyne placed
in the 3-position (Table 5, entries 2 and 5). It is interesting to
note that Larock et al.3 had reported the reaction of 1-phenyl-2-
(trimethylsilyl)acetylene with compound 6 in the presence of
Pd(OAc)2, which afforded exclusively the desilylated product, 2-
Table 4 Synthesis of 2,3-disubstituted-1-indenols using palladacycle 1
Alkyne
Entry
1
4
R1
R2
Time (min)
30 (20b h)
Product(s) (yielda) Table 5 Synthesis of 3,4-disubstituted-2-naphthylamines using pal-
ladacycle 1
Ph
Ph
Alkyne
2
3
SiMe3
Ph
23
Entry
1
R1
R2
Time (min)
26 (48b h)
Product(s) (yielda)
Ph
Ph
n-Pr
n-Pr
38 (20b h)
2
3
4
SiMe3
n-Pr
Ph
Ph
25 (48b h)
30 (48b h)
23 (48b h)
4
5
Ph
Me
25 (15b h)
n-Pr
Me
Ph
Ph
22
26
5
t-Bu
Me
35 (48b h)
6
n-Pr
n-Pr
a
Isolated yields. b Using Pd(OAc)2: 5 mol% Pd, Et3N, TBAC, DMF, 100 ꢀC.3
c
Yield of desilylated coupling product: 2-(2-(phenylethynyl)phenyl)
d
acetonitrile. Yield of unsaturated product: (E)-3-(prop-1-en-1-yl)-4-
a
Isolated yields. b Using Pd(OAc)2: 5 mol% Pd, KOAc, DMF, 100 ꢀC.2
propylnaphthalen-2-amine.
4924 | RSC Adv., 2014, 4, 4921–4929
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
(2-(phenylethynyl)phenyl)acetonitrile, instead of the desired
product 7b. On the contrary, with our reaction conditions,
naphthylamine 7b was obtained as the sole product in 66%
yield (Table 5, entry 2). In addition, the annulation reaction
with 4-octyne provided compound 7c while with Pd(OAc)2
the sole product obtained was (E)-3-(prop-1-en-1-yl)-4-
propylnaphthalen-2-amine (Table 5, entry 3). These results
indicate the palladacycle 1 is generally a suitable palladium
source for the synthesis of 3,4-disubstituted-2-naphthylamines
via the annulation of internal alkynes by (2-iodophenyl)
acetonitrile.
Heteroannulation of haloaniline and derivatives with internal
alkynes
To investigate the general usefulness of palladacycle 1 in
annulation chemistry, we extended our studies to the hetero-
annulation of internal alkynes for the formation of C–N bonds
in the synthesis of 2,3-disubstituted indoles and azaindoles.
The results were gratifying as the heteroannulation process with
palladacycle 1 gave product 9 as a single regioisomer in gener-
ally higher yields than other palladium sources (Table 6). Earlier
studies by Monguchi et al.4c have shown that N-acetyl group of
substrate 8b was labile during the heteroannulation reaction
Table 6 Synthesis of 2,3-disubstituted-1-indoles and 2,3-disubstituted-5-azaindoles using palladacycle 1
Alkyne
R1
Alkyne
R1
Product(s)
(yielda)
Time
(min)
Product(s)
(yielda)
Entry
1
8
R2
Time (min)
Entry
8
8
R2
Ph
Ph
30 (7b h, 10c h, 24d h)
Ph
Ph
Me
18 (24e h)
30 (15g h)
25
2
3
SiMe3 Ph
22 (16e h)
9
Ph
n-Pr
n-Pr 20 (9c h, 20e h, 12f h)
10
SiMe3 Ph
4
5
6
Ph
Me
Me
28
11
12
13
n-Pr
Ph
n-Pr 22 (15g h)
t-Bu
24 (24e h)
Me
Me
30
26
SiMe3 Ph
15
t-Bu
7
n-Pr
n-Pr 22 (24e h)
a
b
c
Isolated yields. Reaction conditions: palladacycle 1, Na2CO3, TBAB, DMF, conventional heating (130 ꢀC). Using 4,40-dichlorobenzophenone
d
oxime palladacycle: 1 mol% Pd, K2CO3, TBAB, DMF, 130 ꢀC.9g Heterogeneous catalysis using Pd/C: 2 mol% Pd, LiCl, Na2CO3, DMPU, 120 ꢀC.11c
e
f
Using Pd(OAc)2: 5 mol% Pd, TBAC, DMF, 100 ꢀC.4a Using Ni(cod)2 (10 mol%), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (10 mol%),
g
LiOt-Bu, toluene, 100 ꢀC.9e Using Pd(dppf)2Cl2: 5 mol% Pd, LiCl, Na2CO3, DMF, 100 ꢀC.5
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 4921–4929 | 4925

View Article Online
RSC Advances
Paper
Table 7 Synthesis of 3,4-disubstituted isoquinoline using palladacycle 1 Table 8 Synthesis of 3,4-disubstituted isocoumarins using pallada-
cycle 1
Alkyne
Time
(min)
Product
(yielda)
Entry 10
R1
R2
Alkyne
R1
Time
(min)
Product(s)
(yielda)
Entry
1
R2
1
Ph
Ph 25 (24b h)
Ph
Ph
27 (216b h)
23 (84b h)
20
2
3
SiMe3 Ph 17 (21b h)
Ph
Me 20 (21b h)
2
3
4
SiMe3
n-Pr
Ph
Ph
4
n-Pr
n-Pr 28 (24b h)
n-Pr
Me
18
5
Ph
Me 30 (29b h)
5
t-Bu
Me
20 (24b h)
a
Isolated yields. b Using Pd(OAc)2: 5 mol% Pd, 10 mol% PPh3, Na2CO3,
c
DMF, 100 ꢀC.6 Desilyated product: 3-phenylisoquinoline.
a
b
Isolated yields. Using Pd(OAc)2: 5 mol% Pd, Na2CO3, LiCl, DMF,
c
100 ꢀC.7 CH3CN as solvent.
with Pd/C in the presence of LiCl, Na2CO3 and DMPU. Thus the
N-deacylated product was obtained as the major product.
However with palladacycle 1, the heteroannulation process
proceeded without decomposition of the acetyl moiety and the
desired N-acetylindole was afforded in good yields (Table 6,
entries 6–8). The same trend of regioselectivity was also
observed as discussed previously (Table 6, entries 2, 4–6, 8, 10,
12 and 13).
minor isomer in 6% yield (Table 7, entry 5). These observations
were consistent with previously reported results.6
Heteroannulation of halobenzoates with internal alkynes
Next we explored the possibility of using the heteroannulation
reaction for the formation of C–O bond. This reaction was rst
exemplied in the synthesis of 3,4-disubstituted isocoumarin
13 via the palladacycle 1 catalyzed heteroannulation of methyl
Heteroannulation of haloimines
Besides aniline-based substrates, imine-based substrate, such 2-iodobenzoate 12 with internal alkynes (Table 8). Compound
as tert-butylimine 10, was also successfully applied to the 13 was obtained in good yields and, as in previous annulation
annulation of aryl- and alkyl-substituted alkynes to provide 3,4- reactions with palladacycle 1, the reaction proceeded in a
disubstituted isoquinoline 11 (Table 7). However when imine regiospecic manner with unsymmetrical alkynes to provide
10a was annulated with trimethylsilyl-substituted alkyne, the the isomer with the more hindered substituent of the alkyne
only product was the desilylated compound 11b (Table 7, placed in the 3-position (Table 8, entries 2, 4 and 5).
entry 2). In addition, annulation of imine 10b with 1-phenyl-1-
To investigate other examples of C–O bond formation in the
propyne also occurred with good regioselectivity to afford 11e heteroannulation reaction, we applied the reaction to benzylic
in 69% yield, whereas compound 11e0 was obtained as the alcohol 14a, 2-iodophenol 14b, and their derivatives (Table 9). It
4926 | RSC Adv., 2014, 4, 4921–4929
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Table 9 Synthesis of 3,4-disubstituted-1H-isochromenes and 2,3-
disubstituted benzofurans using palladacycle 1
14b with internal alkynes also proceed in a regiospecic manner
providing solely the isomer with the bulky substituent of the
alkyne on the carbon that is adjacent to the oxygen (Table 9,
entries 2, 3, 5 and 6). When the reactions were carried out under
the same condition using o-iodophenol 14b1 and derivative
14b2, the corresponding benzofuran 15g was obtained in high
yields (Table 9, entries 7 and 8). In both examples, excellent
regioselectivity was observed.
Alkyne
Time
(min)
Product(s)
(yielda)
Entry
1
14
R1
R2
Recycling of palladacycle 1
Finally we investigated the possibility of recycling and reusing
palladacycle 1 from the annulation reactions for the formation
of C–C, C–N and C–O bonds. These three different annulation
reactions were performed under the optimized reaction condi-
tion and the recycling experiments were carried out over 5 cycles
(Table 10). Gratifyingly, the recovered palladacycle 1 was
indistinguishable from the original precatalyst and showed a
slow decline in catalytic activity aer multiple recovery steps.
The recycling experiments were also followed by comparing the
yields in each cycle aer a xed reaction time and determining
the amount of unreacted aryl halide as well as the recovery of
palladacycle 1. Recovery of palladacycle 1 was good except for
the h cycle and ICP-OES analysis of the crude product indi-
cated that the Pd content was low.
Ph
Ph
35 (24b h)
2
3
SiMe3
Ph
22
t-Bu
Me
25 (20b h)
4
5
6
7
Ph
Ph
Ph
Me
Me
40
Conclusions
A uniform and environmentally benign procedure for the
palladium-catalyzed annulation of a variety of functionalized
aryl halides with internal alkynes in aqueous medium under
microwave irradiation has been developed. Both symmetrical
and unsymmetrical internal alkynes bearing alkyl, aryl and
silyl groups are suitable for this chemistry. This methodology
could be applied to the syntheses of 2,3-disubstituted
1-indenones, 1-indenols, 1-indoles, 5-azaindoles, and benzo-
furans, as well as 3,4-disubstituted 2-naphthylamines,
isoquinolines, isocoumarins, and 1H-isochromenes The
annulation reactions exhibit excellent regioselectivity
providing only one or a major product where the bulkiest
group is on the 2-position for 2,3-disubstituted compounds or
3-position for 3,4-disubstituted compounds. Recycling
was also possible with palladacycle 1 which could be reused
ve times in an annulation reaction. Palladium leaching was
also low.
SiMe3
t-Bu
t-Bu
30
40 (48b h)
35 (24b h)
8
t-Bu
Me
27
a
Isolated yields. b Using Pd(OAc)2: 5 mol% Pd, Na2CO3 or K2CO3, DMF,
100 ꢀC.8
Experimental
General procedures
was observed that the heteroannulation of the oxygen analogs
14a and 14b with internal alkynes proved slightly more difficult All chemicals purchased were used without further purication.
than analogous reactions with the nitrogen analogs 8 and 10, Palladacycle 1 was synthesized according to previously reported
and generally a longer reaction time was required. In addition, procedure.13a Starting materials 8b,4 10,16 14a,17 and 16b (ref. 18)
comparison of the heteroannulation reactions of 14a1 and 14a2 were synthesized according to literature procedures. Moisture-
showed that the presence of a dimethyl substituent on the sensitive reactions were carried out under nitrogen with
benzylic position appears to shorten the reaction time although commercially obtained anhydrous solvents. Analytical thin-
higher yields of benzopyrans 15 were obtained with 14a2. As in layer chromatography (TLC) was carried out on precoated
previous annulation reactions, the heteroannulation of 14a and F254 silica plates and visualized with UV light. Column
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 4921–4929 | 4927

View Article Online
RSC Advances
Paper
Table 10 Recycling of palladacycle 1a
Pd leachingd
(mg Pd per g product)
Cycle
Time (min)
Yield of productb (%)
Recovered 1c (wt%)
1
2
3
4
5
30
38
48
60
75
79 (79e, 0f)
75 (70e, 10f)
70 (59e, 17f)
67 (51e, 25f)
61 (45e, 31f)
89 (89e)
84 (84e)
79 (79e)
76 (76e)
55 (62e)
0.23
0.23
0.23
0.17
0.15
1
2
3
4
5
28
33
41
52
65
78 (78g, 0f)
74 (70g, 5f)
71 (64g, 12f)
68 (56g, 20f)
63 (48g, 29f)
94 (94g)
91 (92g)
85 (89g)
81 (81g)
60 (68g)
0.41
0.38
0.41
0.42
0.39
1
2
3
4
5
27
31
37
48
60
79 (79h, 0f)
76 (72h, 10f)
73 (68h, 13f)
69 (60h, 18f)
63 (51h, 25f)
90 (90h)
85 (87h)
86 (86h)
83 (83h)
73 (79h)
0.24
0.16
0.31
0.18
0.54
a
b
c
d
Using palladacycle 1 (1 mol% Pd), Na2CO3, TBAB, H2O, M.W. 150 ꢀC. Isolated yields. Recovered via F-SPE. Determined by ICP-OES of the
crude product. e M.W. for 30 min. f Recovered aryl halide. g M.W. for 28 min. h M.W. for 27 min.
chromatography was performed with silica (Merck, 230–400 organic layer was dried over anhydrous MgSO4, ltered,
mesh). F-SPE was performed with FluoroFlash® silica gel (40 concentrated and puried by column chromatography.
micron). 1H and 13C NMR spectra were recorded at 298 K.
Chemical shis are expressed in terms of d (ppm) relative to the
internal standard tetramethylsilane (TMS). Mass spectra were
recorded under EI or ESI mode. Microwave reactions were per-
formed on the Biotage Initiator™ microwave synthesizer in
quartz pressure tubes. Pd leaching values were obtained on a
Dual-view Optima 5300 DV (inductively coupled plasma) ICP-
OES system.
General procedure for the recycling experiment using F-SPE
Recycling experiments were carried out on a 1.25 mmol scale
using the general procedure described above. The crude
product was rst diluted with THF–H2O ¼ 8 : 2 (1 mL) and
loaded into a F-SPE uorous silica column (column diameter:
2.20 cm; amount of uorous silica required: 10% of crude
product by weight). The crude product was then eluted using
THF–H2O ¼ 8 : 2 (30 mL) as eluent and the palladacycle 1 (see
Table 10 for amount of recovered 1) was subsequently eluted
with THF (20 mL). The uorous silica was regenerated and
reused (5 times) aer washing with acetone (10 mL). For
General procedure for the palladium-catalyzed annulation of
internal alkyne under microwave irradiation
A mixture of the functionalized aryl halide (0.25 mmol), internal elemental analysis of Pd leaching, a small volume of a solution
alkyne (1.5 equivalents for solid alkyne or 3 equivalents for liquid of the crude product was concentrated and analysed by ICP-
alkyne), TBAB (81 mg, 0.25 mmol), Na2CO3 (53 mg, 0.50 mmol), OES. To determine the amount of product formed aer each
palladacycle 1 (1 mol% Pd) and water (1.0 mL) was heated in a recycling experiment, the solution of crude product was
pressure tube at 150 ꢀC under microwave irradiation. The reac- concentrated, diluted with EtOAc (20 mL) and washed with
tion was monitored by TLC. When the reaction has completed, water (10 mL). The organic layer was dried over anhydrous
the reaction mixture was cooled to room temperature, poured MgSO4, ltered, concentrated and then puried by column
into EtOAc (20 mL) and washed with water (3 ꢂ 10 mL). The chromatography.
4928 | RSC Adv., 2014, 4, 4921–4929
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Palladium in Organic Synthesis, Springer-Verlag, Berlin,
2005, p. 147; (e) Y. Yoshida, T. Kurahashi and
S. Matsubara, Chem. Lett., 2011, 40, 1067; (f) R. P. Korivi
and C.-H. Cheng, J. Org. Chem., 2006, 71, 7079; (g)
Acknowledgements
This research is supported by grants from the Ministry of
Education (Singapore) (MoE Tier 2: R-143-478-112 to Y. Lam)
and National Science Council of Taiwan (NSC 101-2113-M-002-
007 to L.-C.L.).
´
D. A. Alonso, C. Najera and M. C. Pacheco, Adv. Synth.
Catal., 2002, 344, 172.
10 (a) E. B. Mubofu, J. H. Clark and D. Macquarrie, Green Chem.,
2001, 3, 23; (b) D. Rosario-Amorin, X. Wang, M. Gaboyard,
Notes and references
´
´
R. Clerac, S. Nlate and K. Heuze, Chem. – Eur. J., 2009, 15,
12636.
1 R. C. Larock and M. J. Doty, J. Org. Chem., 1993, 58, 4579.
2 L. G. Quan, V. Gevorgyan and Y. Yamamoto, J. Am. Chem.
Soc., 1999, 121, 3545.
11 (a) N. Batail, V. Dufaud and L. Djakovitch, Tetrahedron Lett.,
2011, 52, 1916; (b) H.-C. Zhang, K. K. Brumeld and
B. E. Maryanoff, Tetrahedron Lett., 1997, 38, 2439; (c)
Y. Monguchi, S. Mori, S. Aoyagi, A. Tsutsui, T. Maegawa
and H. Sajiki, Org. Biomol. Chem., 2010, 8, 3338; (d)
L. Djakovitch, N. Bartail and M. Genelot, Molecules, 2011,
16, 5241.
3 Q. Tian, A. A. Pletnev and R. C. Larock, J. Org. Chem., 2003,
68, 339.
4 (a) R. C. Larock, E. K. Yum and M. D. Refvik, J. Org. Chem.,
1998, 63, 7652; (b) D. Zhang, E. K. Yum, Z. Liu and
R. C. Larock, Org. Lett., 2005, 7, 4963; (c) Y. Monguchi,
S. Mori, S. Aoyagi, A. Tsutsui, T. Maegawa and H. Sajiki,
Org. Biomol. Chem., 2010, 8, 3338.
5 F. Ujjainwalla and D. Warner, Tetrahedron Lett., 1998, 39,
5355.
6 K. R. Roesch, H. Zhang and R. C. Larock, J. Org. Chem., 2001,
66, 8042.
12 (a) J.-M. Vincent, Top. Curr. Chem., 2012, 308, 153; (b)
´
´
I. T. Horvath and J. Rabai, Science, 1994, 266, 72.
13 (a) W. Susanto, C.-Y. Chu, W. J. Ang, T.-C. Chou, L.-C. Lo and
Y. Lam, Green Chem., 2012, 14, 77; (b) W. Susanto, C.-Y. Chu,
W. J. Ang, T.-C. Chou, L.-C. Lo and Y. Lam, J. Org. Chem.,
2012, 77, 2729.
14 W. Zhang and D. P. Curran, Tetrahedron, 2006, 62, 11837.
15 M. A. K. Khalil, R. A. Rasmussen, J. A. Culbertson, J. M. Prins,
E. P. Grimsrud and M. J. Shearer, Environ. Sci. Technol., 2003,
37, 4358.
16 K. R. Roesch and R. C. Larock, J. Org. Chem., 1998, 63,
5306.
7 R. C. Larock, M. J. Doty and X. Han, J. Org. Chem., 1999, 64,
8770.
8 R. C. Larock, US5596100A, 19970121, 1997.
9 (a) G. Zeni and R. C. Larock, Chem. Rev., 2006, 106, 4644; (b)
Y. Wang, L. Liu and L. Zhang, Chem. Sci., 2013, 4, 739; J. J. Li,
Name Reactions in Heterocyclic Chemistry II, John Wiley &
Sons, Inc., Hoboken, New Jersey, 2011, p. 146; (c) D. Yue
and R. C. Larock, J. Org. Chem., 2002, 67, 1905; (d) J. Tsuji,
17 Y. C. Fan and O. Kwan, Org. Lett., 2012, 14, 3264.
18 H. Miao and Z. Yang, Org. Lett., 2000, 2, 1765.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 4921–4929 | 4929