Water-triggered, counter-anion-controlled, and silver-phosphines complex-catalyzed stereoselective cascade alkynylation/cyclization of terminal alkynes with salicylaldehydes

Article abstract of DOI:10.1021/jo900079u

A highly efficient alkynylation-cyclization of terminal alkynes with salicylaldehydes leading to substituted 2,3-dihydrobenzofuran-3-ol derivatives was developed by using Cy₃P-silver complex as catalyst in water. Counter anions in the silver co

Full text of DOI:10.1021/jo900079u

Water-Triggered, Counter-Anion-Controlled, and Silver-Phosphines
Complex-Catalyzed Stereoselective Cascade Alkynylation/Cyclization
of Terminal Alkynes with Salicylaldehydes
Min Yu,†,# Rachid Skouta,‡,# Lei Zhou,‡,§ Huan-feng Jiang,§ Xiaoquan Yao,*,† and
Chao-Jun Li*,‡
Department of Applied Chemistry, School of Material Science and Engineering, Nanjing UniVersity of
Aeronautics and Astronautics, Nanjing 210016, P. R. China, Department of Chemistry, McGill UniVersity,
Montreal, QC, Canada H3A 2K6, and College of Chemistry, South China UniVersity of Technology,
Guangzhou 510640, P. R. China
yaoxq@nuaa.edu.cn; cj.li@mcgill.ca
ReceiVed January 15, 2009
A highly efficient alkynylation-cyclization of terminal alkynes with salicylaldehydes leading to substituted
2,3-dihydrobenzofuran-3-ol derivatives was developed by using Cy3P-silver complex as catalyst in water.
Counter anions in the silver complex proved to be the key factor to Z/E stereoselectivity control. Aurones
can also be obtained effectively from the cascade reaction followed by oxidation without further
purification.
Introduction
propargylic alcohols.3 Compared with the classical method using
stoichiometric metal acetylides,4 an alternative and more atom-
economical approach involves the catalytic addition of terminal
alkynes to aldehydes. Recently, various catalytic additions of
alkynes to aldehydes were reported by Carreira,5 Shibasaki,6
and many others. During our earlier studies on the silver-
catalyzed alkynylation of aldehydes in water,7 we found that
Catalytic nucleophilic addition with the direct utilization of
C-H bonds in water provides a highly atom-economical and
environmentally friendly approach to form C-C bonds, which
avoids the utilization of stoichiometric amounts of metal and
halides when compared to classical methods.1,2 As a Grignard-
type reaction, the addition of terminal alkynes to aldehydes is
of great interest because of the versatility of the corresponding
(3) For a review, see: Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J.
Org. Chem. 2004, 4095.
(4) For a recent example, see: (a) Kang, Y.-F.; Wang, R.; Liu, L.; Da, C.-S.;
Yan, W.-J.; Xu, Z.-Q. Tetrahedron Lett. 2005, 46, 863. (b) Fang, T.; Du, D.-
M.; Lu, S.-F.; Xu, J.-X. Org. Lett. 2005, 7, 2081.
† Nanjing University of Aeronautics and Astronautics.
‡ McGill University.
§ South China University of Technology.
# These authors contributed equally to this work.
(1) (a) For recent reviews on C-H activations, see: Dyker, G. Angew. Chem.,
Int. Ed. 1999, 38, 1698. Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.;
Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001, 123, 10935. Chen, H.; Schlecht,
S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287, 1995. Goldman, A. S. Nature
(London) 1993, 366, 514. Crabtree, R. H. J. Organomet. Chem. 2004, 689, 4083.
(f) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. (b) For
atom-economy, see: Trost, B. M. Science 1991, 254, 1471. Trost, B. M. Angew.
Chem., Int. Ed. 1995, 34, 259. Anastas, P. T.; Warner, J. C. Green Chemistry:
Theory and Practice; Oxford University Press, New York, 2000.
(2) For Grignard-type reactions utilizing C-H bonds directly in water, see:
Herrer´ıas, C. I.; Yao, X.; Li, Z.; Li, C.-J. Chem. ReV. 2007, 107, 2546.
(5) For a review on the zinc acetylide system, see: (a) Frantz, D. E.; Fa¨ssler,
R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000, 33, 373. For a catalytic
system, see: (b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687. (c) Fa¨ssler, R.; Tomooka, C. S.; Frantz, D. E.; Carreira, E. M. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5843. See also: (d) Jiang, B.; Chen, Z.; Tang, X.
Org. Lett. 2002, 4, 3451. For stoichiometric additions to aldehyde, see: (f) Frantz,
D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806. (g) Boyall,
D.; Frantz, D. Z.; Carreira, E. M. Org. Lett. 2002, 4, 2605.
(6) Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki, M. Org. Lett.
2005, 7, 1363.
(7) Yao, X.; Li, C.-J. Org. Lett. 2005, 7, 4395.
3378 J. Org. Chem. 2009, 74, 3378–3383
10.1021/jo900079u CCC: $40.75 2009 American Chemical Society
Published on Web 04/03/2009

Alkynylation/Cyclization of Terminal Alkynes
TABLE 1. Catalytic Alkynylation-Cyclization of Salicylaldehyde with Phenylacetylenea
entry
catalyst
conditions
resultsb
1
2
3
4
5
6
7
8
Me3PAuCl
water, i-Pr2NEt 20 mol %, 100 °C
water, i-Pr2NEt 20 mol %, 100 °C
water, i-Pr2NEt 20 mol %, 100 °C
water, i-Pr2NEt 20 mol %, 100 °C
water, i-Pr2NEt 20 mol %, 100 °C
water, i-Pr2NEt 20 mol %, 100 °C
water, i-Pr2NEt 20 mol %, 100 °C
water, i-Pr2NEt 20 mol %, 100 °C
NDc
NDc
NDc
12%
trace
trace
trace
14%
22%
10%
NDc
NDc
trace
trace
trace
20%
31%
67%
59%
77%
Me3PAuCl/AgOTf (1:1.1)d
Ph3PAuCl
Ph3PAgCl
Ph3PAgBr
Ph3PAgI
Ph3P/AgOTf (1.1:1)d
n-Bu3P/AgCl (1.2:1)d
Cy3PAgCl
9
water, i-Pr2NEt 20 mol %, 100 °C
water, Et3N 20 mol %, 100 °C
water, i-Pr2NEt 20 mol %, 100 °C
10
11
12
13
14
15
16
17
18
19
20
Cy3PAgCl
Cy3P/CuCl (1.2:1)d
Cy3PAgCl
MeCN, i-Pr2NEt 20 mol %, 100 °Ce
water-toluene, i-Pr2NEt 20 mol %, 100 °Ce
water-EtOH, i-Pr2NEt 20 mol %, 100 °Cf
water-dioxane, i-Pr2NEt 20 mol %, 100 °Cf
water-DCE, i-Pr2NEt 20 mol %, 100 °Ce
water-CH2Cl2, i-Pr2NEt 20 mol %, 100 °Ce
water-CH2Cl2, i-Pr2NEt 20 mol %, 60 °Cg
water, phenylacetylene (4 equiv), i-Pr2NEt 20 mol %, 100 °C
water, phenylacetylene (4 equiv), i-Pr2NEt 20 mol %, 80 °Ch
Cy3PAgCl
Cy3PAgCl
Cy3PAgCl
Cy3PAgCl
Cy3PAgCl
Cy3PAgCl
Cy3PAgCl
Cy3PAgCl
a Conditions: salicylaldehyde (0.5 mmol), phenylacetylene (0.75 mmol, 1.5 equiv), catalyst (10 mol %), i-Pr2NEt (20 mol %), water (1.5 mL),
overnight. b Isolated yield. c Not detected. d Catalyst was prepared in situ at room temperature by mixing the two precursors in methylene chloride (0.5
mL) for 2 h, and then the solvent was removed under reduced pressure. e Water/organic solvent (v/v) ) 3:1. f Water/organic solvent (v/v) ) 2:1.
g Reacted for 1 day. h Reacted for 8 h.
the metal acetylides of group IB such as Cu(I), Ag(I), and Au(I),
which were believed to be reactive only to imines8 and inert to
carbonyl,9 could be activated by a phosphine ligand and reacted
with aldehydes. Following this approach, a cascade addition/
cyclization of terminal alkynes with acetylenic aldehydes,
catalyzed by a phosphine-gold(I) complex, led to 1-alkynyl-
1H-isochromenes in water.10 In both examples above, water (as
well as the phosphine ligand) plays a key role to promote the
reaction of metal acetylides and aldehydes.
provides a highly efficient route to these compounds.13 However,
following this method, the starting materials had to be prepared
by using the stoichiometric nucleophilic addition between
salicylaldehydes and lithium acetylides, of which 2 equiv were
required: 1 equiv to quench the proton from the phenol group
and the other to react with the aldehyde.
On the basis of the silver(I)- and gold(I)-catalyzed aldehyde-
alkynylation reaction that we reported earlier,14 herein, we
describe a novel highly efficient and stereoselective approach
to construct the dihydrobenzofuran structure directly from
salicylaldehydes and terminal alkynes by a catalyzed cascade
addition/cyclization reaction, in which a catalytic amount of
silver(I) catalyst is used together with a catalytic amount of a
tertiary amine in water. The counter anions in the catalyst behave
as a switch to control the Z/E selectivity of the reaction.
Furthermore, after extracting from water with an organic solvent,
the organic phase can then be oxidized directly without any
further purification to give aurones.
(Z)-2,3-Dihydrobenzofuran-3-ol derives (3) are key interme-
diates for the syntheses of aurones (5), which have exhibited a
wide range of biological activities and have been used as
antifungal agents, tyrosinase inhibitors, antioxidants, etc.11
Among the reported methods for synthesizing aurones,12 the
gold(I)-catalyzed cyclization of 2-(1-hydroxy-3-arylprop-2-
ynyl)phenols followed by oxidation of the cyclized product 3
with MnO2 reported very recently by Pale and co-workers
(8) For an account on the addition of terminal alkynes to imines, see: (a)
Wei, C.; Li, Z.; Li, C.-J. Synlett 2004, 1472. See also: (b) Wei, C.; Mague,
J. T.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5749. (c) Wei, C.; Li,
C.-J. J. Am. Chem. Soc. 2002, 124, 5683. (d) Wei, C.; Li, C.-J. J. Am. Chem.
Soc. 2003, 125, 9584. (e) Wei, C.; Li, Z.; Li, C.-J. Org. Lett. 2003, 5, 4473. (f)
Li, Z.; Wei, C.; Chen, L.; Varma, R. S.; Li, C.-J. Tetrahedron Lett. 2004, 45,
2443. (g) Li, C.-J.; Wei, C. Chem. Commun 2002, 268. (h) Li, C.-J. Acc. Chem.
Res. 2002, 35, 533. (i) Li, C.-J.; Wei, C. Green Chem. 2002, 4, 39. (j) Zani, L.;
Bolm, C. Chem. Commun. 2006, 4263.
Results/Discussions
In our previous studies on the alkynylation of acetylenic
aldehydes,10 Me3PAuCl provided the best catalytic activity.
However, in the prototype reaction between salicylaldehyde and
phenylacetylene of our current studies, neither alkynylation
product nor further cyclization product was observed after
overnight reaction with Me3PAuCl as a catalyst at 100 °C (entry
(9) It was widely accepted that metal acetylides generated from Group
IB metals could not participate in the nucleophilic CdO addition; see refs
5c and 6.
(10) Yao, X.; Li, C.-J. Org. Lett. 2006, 8, 1953.
(11) For a review, see: Boumendjel, A. Curr. Med. Chem. 2003, 10, 2621.
(12) For selected examples, see: (a) Imafuku, K.; Honda, M.; McOmie,
J. F. W. Synthesis 1987, 199. (b) Thakkar, K.; Cushman, M. J. Org. Chem.
1995, 60, 6499. (c) Garcia, H.; Iborra, S.; Primo, J.; Miranda, M. A. J. Org.
Chem. 1986, 51, 4432. (d) An, Z.-W.; Catellani, M.; Chiusoli, G. P. J. Organomet.
Chem. 1990, 397, 371. (e) Jong, T.-T.; Leu, S.-J. J. Chem. Soc., Perkin Trans.
1 1990, 423.
(13) Harkat, H.; Blanc, A.; Weibel, J.-M.; Pale, P. J. Org. Chem. 2008, 73,
1620.
(14) For recent reviews on silver-catalyzed reactions, see: (a) Yamamoto,
Y. Chem. ReV. 2008, 108, 3199. (b) Weibel, J.-M.; Blanc, A.; Pale, P. Chem.
ReV. 2008, 108, 3149. (c) Halbes-Letinois, U.; Weibel, J.-M.; Pale, P. Chem.
Soc. ReV. 2007, 36, 759. (d) Li, Z.; He, C. Eur. J. Org. Chem. 2006, 4313–
4322.
J. Org. Chem. Vol. 74, No. 9, 2009 3379

Yu et al.
TABLE 2. Catalytic Alkynylation-Cyclization of Salicylaldehydes with Arylacetylenesa
a Conditions: salicylaldehyde (0.25 mmol), phenylacetylene (1 mmol, 4 equiv), Cy3PAgCl (10 mol %), i-Pr2NEt (20 mol %), water (1.5 mL).
b Isolated yield. c 0.5 mmol of salicylaldehyde and 2 mmol of phenylacetylene were used. d Calculated based on the recovered starting material.
e Reaction was carried out in water/CH2Cl2, with 2 equiv of alkyne.
1, Table 1). No reaction was observed with changing either the
counteranions or the ligands (entries 2 and 3, Table 1). When
Ph3PAgCl was used, the desired product was obtained in only
12% yield with a low conversion of the starting material (entry
4, Table 1). Changing the counter ions did not show any
improvement for the reaction (entries 5-7, Table 1).
n-Bu3PAgCl gave results similar to those with Ph3PAgCl (entry
8 vs entry 4, Table 1). Cy3P and Cl- provided the best
combination of ligand and counter anion, and a 22% yield was
observed (entry 9, Table 1). It is worth noting that introduction
of some organic solvents decreased the reactivities, with the
exceptions of DCE and methylene chloride. The desired product
3a was isolated in 67% yield with a mixture of CH2Cl2/water
as solvent at 60 °C for 1 day (entries 12-18, Table 1).15 The
use of 4 equiv of phenylacetylene for 8 h at 80 °C gave the
desired product in 77% yield (entry 20, Table 1). A higher
3380 J. Org. Chem. Vol. 74, No. 9, 2009

Alkynylation/Cyclization of Terminal Alkynes
TABLE 3. Reaction of Salicylaldehyde with Phenylacetylene using AgF/PCy3 as Catalysta
entry
catalyst (mol %)
conditions
yield of 3a:4a, %b
1
2
3
AgF/PCy3 (10/10)
AgF/PCy3 (5/5)
AgF/PCy3 (2.5/2.5)
AgF (5)
water, i-Pr2NEt 20 mol %, 100 °C, 1 d
water, i-Pr2NEt 10 mol %, 90 °C, 2 d
water, i-Pr2NEt 5 mol %, 90 °C, 2 d
30 only 4a
56 only 4a
49 only 4a
no reaction
4
water, i-Pr2NEt 10 mol %, 90 °C, 2 d
5
6
7
8
9
10
AgF/PCy3 (5/5)
AgF/PCy3 (5/5)
AgF/PCy3 (5/5)
AgF/PCy3 (5/5)
AgF/PCy3 (5/5)
AgF/PCy3 (5/5)
water/toluene, i-Pr2NEt 10 mol %, 90 °C, 2 d
water/EtOH, i-Pr2NEt 10 mol %, 90 °C, 2 d
water/t-BuOH, i-Pr2NEt 10 mol %, 90 °C, 2 d
water/n-BuOH, i-Pr2NEt 10 mol %, 90 °C, 2 d
water/i-PrOH, i-Pr2NEt 10 mol %, 90 °C, 2 d
water/THF, i-Pr2NEt 10 mol %, 90 °C, 2 d
24 (3a:4a ) 2:1)
54 (3a:4a ) 1.2:1)
55 (3a:4a ) 2:1)
74 (3a:4a ) 7.2:1)
80 (3a:4a ) 3.7:1)
82 (3a:4a ) 5.3:1)
a Reaction conditions: salicylaldehyde (1 mmol), phenylacetylene (2 mmol), AgF (5 mol %), Cy3P (5 mol %), water (5 mL). If organic cosolvent was
used: water/org sol ) 4.5/0.5 (mL/mL). b NMR yield with CH3NO2 as internal standard.
TABLE 4. Silver-Catalyzed Annulation of Aldehydes with Alkynesa
a Conditions: all reactions were carried out at 90-95 °C for 48 h in a sealed tube under nitrogen, with aldehyde (1 equiv), alkyne (2 equiv), AgF
(5 mol %), PCy3 (6 mol %), i-Pr2NEt (10 mol %) and 5 mL of deoxygenated water. b Isolated yields. c 10 mol % of the catalyst was used.
reaction temperature was not beneficial (entry 19, Table 1).
Interestingly, only Z-isomer was observed in all these reactions.
Subsequently, various salicylaldehydes were reacted with
terminal alkynes under the optimized conditions (Table 2).
Moderate to good yields of the Z-isomers were obtained
selectively. Salicylaldehydes with halides on 5-position proved
to be beneficial to the reaction, and an 83% yield was obtained
with 5-bromo-salicylaldehyde (entries 2 and 4, Table 2).
J. Org. Chem. Vol. 74, No. 9, 2009 3381

Yu et al.
SCHEME 1. Cascade Addition/Cyclization and Oxidation to Aurones
TABLE 5. Silver(Ι)-Catalyzed Cyclization of 6a
However, the yields decreased somewhat with the introduction
of a second halide on 3-position (entries 2 and 4 vs entries 3
and 5, respectively), which might be partly due to the easier
decomposition of the corresponding products under the current
reaction conditions. On the other hand, the presence of tert-
butyl groups seem to slow down the reaction; a much higher
reaction temperature and a lower conversion were observed
(entries 6 and 8, Table 2). The yield also decreased slightly
when tolylacetylene was used instead of phenylacetylene.
However, using a mixture of CH2Cl2/water as solvent increased
the yield of product 3k to 81% (entry 12, Table 2). It should be
noted that all these reactions showed excellent stereoselectivities
for the Z-isomers under these conditions.
entry
solvent
yield of 3d (%)b
1c
2
3
phenylacetylene/water
MeCN
toluene
71
22 (36% conv)
7.4 (12% conv)
a Conditions: all reactions were carried out at 70 °C for 3 h in a
sealed tube under nitrogen, with 6 (0.25 mmol), Cy3PAgCl (10 mol %),
i-Pr2NEt (20 mol %), and 1.5 mL of corresponding solvent. b Isolated
yields. c 1 mmol of phenylacetylene was used.
Surprisingly, when a Cy3PAgF catalyst, generated in situ from
AgF and Cy3P, was used instead of Cy3PAgCl, the E-isomer
4a16 was observed stereoselectively in moderate yield under the
same conditions (entry 1, Table 3). With 5 mol % Cy3PAgF
catalyst at 90 °C, 4a was obtained stereoselectively in 56% yield
(entry 2, Table 3). Introducing some organic cosolvents,
although increasing the yields, switched the selectivity from the
E-isomer to predominantly the Z-isomers (entries 5-10, Table
3). With 10% THF in water as solvent, up to 82% combined
yield of 3a and 4a was achieved with 3a as the major product
(entry 10, Table 3).
SCHEME 2. Proposed Mechanism for the
Silver(I)-Catalyzed Cascade Alkynylation/Cyclization of
Salicylaldehyde
Subsequently, a variety of salicylaldehydes and arylacetylenes
were examined under the same reaction conditions. The E-
isomers 4a-g were obtained stereoselectively in all cases by
using AgF/PCy3 as catalyst and i-Pr2NEt as base in water at 90
°C. In this reaction, some substituted arylalkynes gave similar
results (entries 1-5, Table 4), whereas the substituent on
salicylaldehyde showed stronger influence on the reactivity. The
reaction of 5-chloro-salicylaldehyde with phenylacetylene and
4-methylphenylacetylene gave the desired products in 77% and
79% yields, respectively (Table 4, entries 6 and 7).
The crude product 3a or 3d, from the cascade reaction on an
enlarged scale, was extracted by CH2Cl2 from water and then
was oxidized by MnO2 directly without further purification. The
final aurone products 5a and 5d were isolated in good yields
(Scheme 1).
To further understand the mechanism of the reaction, prop-
argylic alcohol 6 was prepared via the addition of lithium
phenylacetylide to salicylaldehyde.13 The propargylic alcohol
obtained was investigated in several solvents using Cy3PAgCl
as catalyst under the present conditions (Table 5). The phenyl-
acetylene/water system gave the highest yields compared to
those of other organic solvents (entry 1, Table 5). It is worth
noting that the catalytic cyclization can also proceed with a
moderate yield in acetonitrile (entry 2, Table 5).
species A. The acetylide then reacts with aldehyde to give
intermediate B, in the presence of water, followed by a silver(I)-
promoted trans-attack of phenol to the triple bond to give the
vinylsilver intermediate C. Coordination of the alcohol and
the triple bond to Ag(I) provides a stereochemistry control for
the trans-attack (generating the Z-isomer). The carbon-silver
bond is then protonated to give the final product 3 with
regeneration of the catalyst. However, the model above could
not provide a reasonable explanation for the E-isomer selectivity
with the AgF/Cy3P catalytic system. The investigation of the
exact mechanism is ongoing.
In conclusion, a highly efficient alkynylation-cyclization of
terminal alkynes with salicylaldehydes leading to (Z)-2-ben-
zylidene-2,3-dihydrobenzofuran-3-ol was developed by using
Cy3PAgCl complex as catalyst in water. The E-isomers can also
Thus, a tentative mechanism for the silver(I)-catalyzed
cascade alkynylation/cyclization of salicylaldehydes is described
in Scheme 2. Reaction of terminal alkynes with Cy3AgCl in
the presence of a weak base generates the silver(I) acetylide
3382 J. Org. Chem. Vol. 74, No. 9, 2009

Alkynylation/Cyclization of Terminal Alkynes
Typical Procedure 3 (Entry 1, Table 4). AgF (3.2 mg, 0.025
mmol) and PCy3 (8.4 mg, 0.03 mmol), aldehydes 1a (0.5 mmol),
alkynes 2a (1 mmol), and i-Pr2NEt (8.4 µL, 0.05 mmol) in 5 mL
of deoxygenated water were heated in a sealed tube at 90-95 °C
for 2 d under nitrogen. The reaction mixture was cooled to room
temperature and extracted with EtOAc. The combined organic phase
was dried with Na2SO4 and concentrated under a reduced pressure.
The residue was purified by flash column chromatography on silica
gel (eluent ) hexanes/EtOAc 20-30:1). Compound 4a was
obtained in 56% of yield. 4a: IR (neat, NaCl) νmax 3332, 2977,
2920, 1600, 1493, 1452, 1378, 1321, 1298, 1253, 1170, 1126, 1079,
be obtained stereoselectively with AgF/Cy3P as the in situ
catalyst. Furthermore, the crude product of the cascade reaction
can be oxidized to aurone effectively without any purification.
The detailed mechanism and the scope of the reaction are
currently under further investigations.
Experimental Section
Typical Procedure 1 (Entry 1, Table 2). Cy3PAgCl (21.2 mg,
0.05 mmol, 10 mol %) was mixed with 1.5 mL of distilled water,
53 µL of salicylaldehyde (0.5 mmol), 0.22 mL of phenylacetylene
(2a) (2 mmol, 4 equiv), and 17 µL of i-Pr2NEt (0.01 mmol, 20
mol %) in a sealed tube under nitrogen atmosphere. The mixture
was stirred at room temperature overnight and then was heated to
80 °C (bath temperature) for 8 h. The reaction was stopped and
extracted with ether (3 × 5 mL). The extraction was dried with
Na2SO4 and concentrated under a reduced pressure. The residue
was purified by flash column chromatography on silica gel (eluent
) hexanes/EtOAc 20-30:1). Compound 3a was obtained in 77%
of yield. 3a:13 CA registry no. [1008105-79-0]. IR (KBr): νmax 3414,
1
1041, 945, 885, 843, 802, 775, 742, 698, 537 cm-1; H NMR
(CDCl3, 400 MHz, ppm) δ 7.54-7.36(m, 7H), 7.28-7.22(m, 2H),
6.53(s, 1H), 5.94(b, 1H), 2.77(b, 1H); 13C NMR (CDCl3, 75 MHz,
ppm) δ 158.7, 155.3, 140.5, 128.9, 128.6, 128.3, 127.1, 124.6,
123.1, 121.4, 111.6, 104.3, 70.9; GC/MS m/z (%) 224 (M+), 207
(100), 195, 178, 165, 147, 119, 105, 91, 77, 63, 51; HRMS calcd
for C15H12O2 224.0837, found 224.0834.
Typical Procedure 4 (Scheme 1). Following the procedure
described in Typical Procedure 1, salicylaldehyde (1a) (2 mmol)
reacted with phenylacetylene (2a) (6 mmol) in 3 mL of distilled
water, in the presence of Cy3PAgCl (10 mol %) and i-Pr2NEt (20
mol %). When the reaction was stopped and cooled to room
temperature, 3 mL of CH2Cl2 was added and stirred for several
minutes. The aqueous layer was then removed by pipet and
extracted with CH2Cl2 again (3 mL × 2). The combined organic
1
1683, 1612, 1601, 1479, 1290, 1236, 1088, 1022, 908 cm-1; H
NMR (CDCl3, 400 MHz, ppm) δ 7.74 (d, J ) 7.9 Hz, 2H), 7.50
(d, J ) 7.2 Hz, 1H), 7.42-7.34(m, 3H), 7.28-7.24 (m, 1H),
7.12-7.09 (m, 2H), 6.02 (s, 1H), 5.76 (d, J ) 12 Hz, 1H), 2.32(d,
J ) 12 Hz, 1H); 13C NMR (CDCl3, 100 MHz, ppm) δ 157.8, 157.0,
134.5, 130.6, 128.7, 128.5, 126.9, 126.8, 125.7, 122.9, 110.7, 106.0,
72.5; GC/MS m/z (%) 224 (M+), 223 (100), 207, 178, 147, 131,
120, 103, 89, 77.
17
solution was cooled in an ice bath, and then MnO2 (10 mmol)
was added. The mixture was stirred at room temperature for 2 h
and filtered through Celite. The organic phase was concentrated
under a reduced pressure, and the residue was purified by flash
column chromatography on silica gel (eluent ) hexanes/EtOAc
30-40:1). Compound 5a was obtained in 75.1% of yield. 5a:13
CA registry no. [37542-14-6]. IR (KBr): νmax 3058, 3020, 1713,
1660, 1599, 1477, 1302, 1128 cm-1; 1H NMR (CDCl3, 400 MHz,
ppm) δ 7.95 (d, J ) 7.3 Hz, 2H), 7.83 (d, J ) 7.6 Hz, 1H), 7.67(t,
J ) 8.4 Hz, 1H), 7.51-7.41 (m, 3H), 7.36 (d, J ) 8.3 Hz, 1H),
7.25 (t, J ) 7.5 Hz, 1H), 6.93 (s, 1H); 13C NMR (CDCl3, 100 MHz,
ppm) δ 184.8, 166.2, 146.9, 136.9, 132.3, 131.6, 129.9, 128.9,
124.7, 123.5, 121.7, 113.1, 113.0; GC/MS m/z (%) 222 (M+), 221,
205, 165, 120, 92, 76, 58, 43 (100).
Typical Procedure 2 (Entry 12, Table 2). Cy3PAgCl (21.2
mg, 0.05 mmol), aldehydes (0.5 mmol), alkynes (1 mmol), and
i-Pr2NEt (17 µL, 0.10 mmol) in a mixture of deoxygenated water
and CH2Cl2 (3:1, 2 mL) were heated in a sealed tube at 60 °C
for 24 h under nitrogen. The reaction was stopped and extracted
with ether (3 × 5 mL). The extracted organic layer was dried
with Na2SO4 and concentrated under a reduced pressure. The
residue was purified by flash column chromatography on silica
gel (eluent ) hexanes/EtOAc 15-20:1). Compound 3k was
obtained in 81% of yield by this procedure. 3k: IR (KBr) νmax
3356, 2920, 2855, 2358, 1689, 1610, 1511, 1473, 1237, 1182,
1135, 1099, 1020, 905 cm-1; 1H NMR (CDCl3, 400 MHz, ppm)
δ 7.59 (d, J ) 8.0 Hz, 2H), 7.47 (s, 1H), 7.31 (dd, J ) 2.4, 8.4
Hz, 2H), 7.20 (d, J ) 7.9 Hz, 1H), 7.02 (d, J ) 8.6 Hz, 1H),
6.00 (s, 1H), 5.74 (d, J ) 9.0 Hz, 1H), 2.38(s, 3H), 2.33 (d, J
) 9.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz, ppm) δ 156.3,
155.9, 137.0, 131.3, 130.6, 129.2, 128.7, 128.6, 127.7, 125.8,
111.7, 106.6, 72.3, 21.3; GC/MS m/z (%) 272 (M+), 255, 237,
205, 192, 181, 165, 118 (100), 105, 91; HRMS calcd for
C16H13ClO2 272.0604, found 272.0602.
Acknowledgment. We are grateful to the financial support
from National Natural Science Foundation of China (20602018
to X.Y.). L.Z. thanks the China Scholarship Council for a
visiting scholarship. We are also grateful to the Canada Research
Chair (Tier I) foundation, the CFI, NSERC (to C.-J.L.) and
McGill University for support of this research.
Supporting Information Available: Full characterization
1
data, H and 13C NMR spectra of additional compounds. This
(15) For the heterogeneous reaction on small scales, the substrates tend to
stick on the surface of the stirring bar or the side of the tube, which results in
lower conversions. The introduction of a lower-boiling solvent such as DCE
and methylene chloride together with a higher reaction temperature may be
helpful to keep the substrates in the reaction mixture and increase the yield.
(16) The E-4a stereochemistry was defined by 1D NOE, irradiating the peaks
at 6.53 and 5.94 ppm. For the E-isomer, no NOE effect with each other was
observed. Please see the spectra for Z-3a and E-4a in Supporting Information.
material is available free of charge via the Internet at
http://pubs.acs.org.
JO900079U
(17) Fresh MnO2 was prepared from MnSO4 and KMnO4.
J. Org. Chem. Vol. 74, No. 9, 2009 3383