The Sonogashira coupling of polymer-supported propargylamine with aryl iodides

Article abstract of DOI:10.1002/hlca.200900129

The Sonogashira coupling reaction of polymer-supported propargylamine (= prop-2-yn-1-amine) with aryl iodides in the presence of the [Pd(PPh ₃)₂]Cl₂/CuI catalyst system produces 3-arylprop-1-yn-1-amines smoothly at room temperature (Scheme). When propargylamine is attached on Wang resin through a carbamate linker, the common problems with amino functionality in palladium-catalyzed couplings are overcome. The arylpropynamines are cleaved from the polymer with CF₃COOH and converted into chromatographically easily separable acetamides. Our solid-phase method opens a new pathway toward precursors of pharmacologically interesting arylpropynamines and arylpropanamines

Full text of DOI:10.1002/hlca.200900129

Helvetica Chimica Acta – Vol. 93 (2010)
39
The Sonogashira Coupling of Polymer-Supported Propargylamine with Aryl
Iodides
by Tuomo Leikoski, Sirkku Kallonen, and Jari Yli-Kauhaluoma*
Division of Pharmaceutical Chemistry, Faculty of Pharmacy, P. O. Box 56, FI-00014 University of
Helsinki (phone: þ 358-9-19159170; fax: þ 358-9-19159556; email: jari.yli-kauhaluoma@helsinki.fi)
The Sonogashira coupling reaction of polymer-supported propargylamine (¼ prop-2-yn-1-amine)
with aryl iodides in the presence of the [Pd(PPh3)2]Cl2/CuI catalyst system produces 3-arylprop-1-yn-1-
amines smoothly at room temperature (Scheme). When propargylamine is attached on Wang resin
through a carbamate linker, the common problems with amino functionality in palladium-catalyzed
couplings are overcome. The arylpropynamines are cleaved from the polymer with CF3COOH and
converted into chromatographically easily separable acetamides. Our solid-phase method opens a new
pathway toward precursors of pharmacologically interesting arylpropynamines and arylpropanamines.
Introduction. – Aryl- and heteroarylpropanes are common precursors of bio-
logically important natural products, e.g., of lignin [1] and lignans [2]. In addition, some
3-aryl- or 3-heteroarylpropan-1-amine derivatives have been associated with central
nervous system stimulating [3], antimalarial [4], positive inotropic [5], and antifungal
[6] properties. We embarked on the solid-phase Sonogashira coupling reactions of
polymer-bound propargylamine (¼ prop-2-yn-1-amine) with various aryl iodides. The
3-arylpropargylamines obtained in this coupling reaction can be reduced into 3-
arylpropan-1-amines of interest. On the other hand, substituted arylpropargylamines
themselves are interesting compounds since some of them, or their metabolites, possess
selective inhibitory activity toward physiologically significant enzymes, such as
aldehyde dehydrogenase [7] and monoamine oxidase B [8].
The Sonogashira coupling is an efficient palladium-catalyzed method for con-
structing aryl- and heteroarylacetylenes [9]. This reaction has been widely studied in
liquid-phase synthesis, and due to its general efficiency, e.g., high yields, tolerance of a
wide range of functional groups, and a simple one-step procedure, it has in most
applications replaced the analogous reaction of copper acetylide, the Castro – Stephens
reaction [10]. Although the Sonogashira coupling in solid-phase reactions has been
studied to a lesser extent, there are substantial amount of reports, where the benefits of
the use of polymer-supported reagents have been combined with the high performance
of this reaction [11 – 24]. On the other hand, both the aryl iodide and the acetylene
components have been successfully used as polymer-bound reactants. For example,
Moore and co-workers generated a resin-bound terminal acetylene by deprotecting the
trimethylsilyl group with Bu4NF, and subjected it to Sonogashira conditions with
(trimethylsilyl)acetylene-funtionalized aryl iodides [11]. After repeating the reaction
cycles, oligomeric arylacetylenes were obtained as final products. Huang and Tour
applied a related sequence-specific methodology in solid-phase synthesis of linear,
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 93 (2010)
oligomeric arylacetylenes by subsequently introducing aryl diiodides and monopro-
tected phenylenebis[acetylenes] [16]. Bolton et al. used Sonogashira coupling in the
arylation of a polymer-bound olefinic acetylene prior to its Pauson – Khand cyclization
[12]. Tulla-Puche and Barany employed an interesting way of proceeding, where both
reactants were attached on different resins with Wang and allyl linkages [24]; treatment
with Pd(0) cleaved the allyl-linked component which subsequently underwent a resin-
to-resin transfer Sonogashira reaction.
In addition to the general usefulness of solid-phase syntheses owing to the
convenient preparation of combinatorial compound libraries by automatization, to
their simple reaction conditions and product isolation, as well as to their safety in large
scale preparations, the solid-phase versions of Sonogashira coupling possess some extra
advantages. For example, diyne and other by-product formation is almost avoided when
the acetylenic reactant is covalently bound to the polymer. Additionally, reactive
functional groups can be protected by using them as attachment sites.
So far, there are no reports of the Sonogashira reaction of polymer-bound
unsubstituted propargylamines. De Mesmaeker and co-workers studied the coupling of
propargylamine with aryl iodides in solution and observed formation of the desired
arylacetylene in an excellent yield, but only when the propargylamine was introduced
into the reaction as a (tert-butoxy)carbonyl-protected derivative [25]. Additionally,
Khan and Grinstaff used amide and carbamate derivatives of propargylamine, among
them N-(trifluoroacetyl)- and N-[(tert-butoxy)carbonyl]propargylamine, in the cou-
pling reaction with polymer-bound 5-iodouridines in a modification study of
oligonucleotides [14].
To avoid polymer-bound propargylamine acting as a competing base with the
tertiary amine, typically Et3N, used in the coupling, we concentrated our efforts on
reactions of propargylamine attached to the Wang resin through a carbamate linkage
(Scheme). Among the several reactions available to bind amines covalently to the
polymer, the carbamate method has been used in syntheses of low molecular-mass
compounds, e.g., 1,2,3-triazoles [26], and in the solid-phase synthesis of oligomeric
peptides [27]. On the other hand, this method enables quantitative cleavage of the
amine products from the polymeric support under relatively mild conditions with 50%
CF3COOH in CH2Cl2. Herein, we report the use of Wang-resin-bound propargylamine
as a masked amino derivative in the Sonogashira coupling reaction with aryl iodides
and the isolation and purification of the 3-arylpropargylamine products as easily
separable acetamides (Scheme).
Results and Discussion. – We started our studies by searching a suitable polymeric
support and an effective and reproducible attachment method for propargylamine. For
example, we coupled propargylamine to trityl chloride resin by the corresponding
1
method for 2-chlorotrityl chloride resin [28]. The H-NMR spectrum of the cleaved
CF3COOꢀ salt was identical to the corresponding salt prepared from commercial
propargylamine. However, the standard Sonogashira conditions with [Pd(PPh3)4] or
[Pd(PPh3)2]Cl2 as a catalyst and CuI as a co-catalyst [18][29] for this polymer-bound
acetylene did not give a trace of the desired arylacetylene. Considering these results
with the studies of De Mesmacker and co-workers [25], it can be assumed that the
probable reason for this failure is the amino functionality in the linkage. Polymer-

Helvetica Chimica Acta – Vol. 93 (2010)
41
Scheme. Coupling of Propargylamine to Wang Resin, the Sonogashira Reaction, Cleavage, and
Acetylation
i) 4-Nitrophenyl carbonochloridate, pyridine, CH2Cl2, r.t., 2 h. ii) HCꢁCCH2NH2, DMF, 08 to r.t., 20 h.
iii) ArI (3 – 5 equiv.), [Pd(PPh3)2]Cl2 (0.2 equiv.), CuI (0.4 equiv.), Et3N/1,4-dioxane 1:2, r.t., 20 – 73 h.
iv) CF3COOH/CH2Cl2 1:1, r.t., 2 h. v) iPr2NEt/Ac2O 1:1, cat. N,N-dimethylpyridin-4-amine (DMAP),
r.t., 2 h.
supported propargylamine is a secondary amine, which is a stronger base than free
propargylamine. Therefore, it is possible that the polymer-bound propargylamine is
acting in the reaction as an amine base, analogously to the Et3N used the in solution
phase, rather than as an acetylenic nucleophile. On the other hand, suppression of the
coupling reaction caused by direct interaction of the N-atom with the palladium
complex, as postulated by Santelli and co-workers [30], cannot be excluded. In
´
addition, Erdelyi and Gogoll discussed about the amine-mediated decomposition of the
catalyst as a competing process [19]. Moreover, steric factors can play an important
role in these reactions. Nakamura et al. performed straightforward Sonogashira
couplings in solution with heteroaryl bromides and N,N-diisopropylpropargylamine
[31]. Additionally, Santelli and co-workers obtained the best results with bulky, tertiary
amines [30]. Hence, it is conceivable that the bulkiness of the amine overcomes its high
basicity in the reaction.
After these preliminary experiments, we decided to test propargylamine attached to
the Wang resin with a carbamate linker. This polymer-supported amine was routinely
prepared by a two-step procedure [26] from the Wang resin, 4-nitrophenyl carbon-
ochloridate (¼4-nitrophenyl chloroformate), and pyridine in CH2Cl2 and a subsequent
reaction of the isolated 4-nitrophenyl carbonate resin with propargylamine in DMF
(Scheme). The success of the attachment can be monitored by FT-IR by means of the
characteristic terminal-alkyne signals at 3290 cmꢀ1 and 2100 cmꢀ1 and the strong
carbamate C¼O peak at 1710 cmꢀ1. This light yellow Wang-carbamate resin shows the
expected stability in air at room temperature, but it was stored in a desiccator over silica
gel due to the requirements of dry conditions in the subsequent palladium-catalyzed
reactions.
We observed the formation of coupling products from the Wang-carbamate resin
and aryl iodides (see Scheme) with satisfying yields when we applied the Sonogashira
procedure for polymer-bound aryl iodide with phenylacetylene in solution [15]; in this
method, [Pd(PPh3)2]Cl2 and CuI constitute the catalyst system and dry 1,4-dioxane/
Et3N 2 :1 the solvent. Three- to five-fold excess of aryl iodides over the polymer-bound
propargylamine was used in our studies. The couplings proceeded at room temperature,

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Helvetica Chimica Acta – Vol. 93 (2010)
typically within 20 – 73 h. The use of amine base as the co-solvent was crucial. Our
initial trials of the same Wang-carbamate resin with iodobenzene in THF with
[Pd(PPh3)2]Cl2 and in DMF with [Pd(PPh3)4], wherein only ca. 1.5 equiv. of Et3N with
respect to the polymer-bound propargylamine was used, did not give a trace of the
desired coupling product.
After the cleavage of the polymer moiety with CF3COOH/CH2Cl2 1:1, the 3-
arylpropargylamines were liberated from their CF3COOꢀ salts with N,N-diisopropyl-
ethylamine and immediately acetylated with Ac2O (Scheme). To ensure complete
acetylation within 2 h, a catalytic amount of N,N-dimethylpyridine-4-amine (DMAP)
was added into the mixture. The products were acetylated to facilitate purification by
the subsequent flash chromatography thus avoiding the sluggish separation of free
amines by silica gel column chromatography. A typical eluent system was an AcOEt/
acetone gradient, which gave good separation of these relatively polar acetamides.
However, the purity of the acetamide with a MeO group at the meta position of the aryl
moiety (Table, Entry 11) was, according to LC/UV detection at 210 nm, only 79% due
to inseparable impurities.
Table. Yields and Primary Analysis Data of N-(3-Arylpropargyl)acetamides Obtained from Various Aryl
Iodides after Loading of Propargylamine to Wang Resin, Sonogashira Coupling, Cleavage, and
Acetylation
Entry Aryl group
1H-NMR
13C-NMR
FT-IR
Yield [%]d)
d(ArCꢁCCH2)a) d(ArCꢁCCH2)b) C¼O (acetamide) [cmꢀ1]c)
1
2
3
4
5
6
7
8
9
Ph
4.21
82.6; 87.2
80.9; 92.8
81.1; 91.9
76.2; 92.8
80.9; 89.0
81.3; 88.8
81.4; 87.0
79.4; 90.7
81.0; 88.9
81.3; 88.5
82.5; 87.0
1651
1643
1642
1633
1636
1656
1646
1657
1634
1634
1655
41
52
60
55
55
44
15
47
51
36
24
4-NO2C6H4 4.28
4-CNC6H4
2-ClC6H4
3-BrC6H4
3-CHOC6H4 4.25
4-FC6H4 4.18
pyridin-3-yl 4.25
3-ClC6H4
4-ClC6H4
3-MeOC6H4 4.19
4.25
4.28
4.21
4.21
4.20
10
11
a) 300 MHz, (D6)acetone; d, J ¼ 5 – 6 Hz. b) 75 MHz, (D6)acetone. c) KBr pellets. d) Yield of the
isolated acetamide.
In general, the best results were obtained with aryl iodides containing electron-
withdrawing substituents, the highest yield being 60% with 4-iodobenzonitrile, after
loading of propargylamine to Wang resin, coupling, cleavage, and acetylation (Table,
Entry 4). The 1-chloro-2-iodobenzene, and 1-bromo-3-iodobenzene gave both 55%
yield (Entries 4 and 5) of the coupling product after cleavage and acetylation,
suggesting that the position of the substituent at the aromatic ring does not play an
important role in the success of the coupling. Furthermore, the latter reactant showed
total selectivity of the I- over the Br-substituent as a leaving group. The only exception
of the general rule was the reactivity of 1-fluoro-4-iodobenzene: with the high
electronegativity of the F-atom, a better yield than the obtained 15% (Entry 7) would

Helvetica Chimica Acta – Vol. 93 (2010)
43
have been expected. Of course, it is possible that the high electron withdrawal surpasses
unexpected side reactions as well.
The reaction of 4-iodoanisole (¼1-iodo-4-methoxybenzene) did not give the
desired coupling product at all, neither at room temperature overnight nor even after
92 h at 708. However, 3-iodoanisole (¼1-iodo-3-methoxybenzene), where the sub-
stituent acts mainly as s-acceptor, gave a 24% yield after attachement, coupling at
room temperature, cleavage, and acetylation (Entry 11). According to this observation,
the coupling reaction is retarded more strongly when electron density is donated by
conjugation.
In addition, the coupling reaction of 3-iodobenzaldehyde proceeded successfully
(Entry 6). After the cleavage from the polymer, the product was released from its
CF3COOꢀ salt and acetylated immediately at ꢀ 1008. This exceptional acetylation
procedure was applied to avoid rapid polymerization of the aminoaldehyde at room
temperature. The corresponding acetylated derivative obtained could be routinely
purified by silica gel column chromatography. Generally, all the acetylenic acetamides
prepared were sufficiently stable when stored under dry conditions at room temper-
ature.
1
Interpreting the H-NMR spectra of the acetamides derived from the coupling
products is rather straightforward. In all spectra, the CH2 group of the propynyl moiety
gives a d at d 4.2 – 4.3 with a coupling constant of 5 – 6 Hz arising from the coupling with
the amide NH proton. In the case of the 2-chloro-substituted product, also the signal of
the amide NH proton is visible as a broad signal in the aromatic region. In the 13C-NMR
spectrum of the 4-fluoro-substituted product, the F-atom couples strongly to all C-
atoms of the aromatic ring.
Conclusions. – We have combined the advantages of the efficient solid-phase-
synthesis methodology and the wide applicability of palladium-catalyzed coupling
reactions in the Sonogashira reaction of polymer-supported propargylamine with aryl
iodides. The amino group that is problematic in the Sonogashira coupling is easily
converted into a mildly cleavable carbamate linker at the attachment to the Wang resin.
The reactions proceed generally with moderate to good yields at room temperature,
and the use of base, e.g., Et3N, as the co-solvent is necessary. Our solid-phase method
provides new possibilities for the syntheses of pharmacologically interesting carbocy-
clic and heterocyclic 3-arylprop-2-yn-1-amines and 3-arylpropan-1-amines.
We thank the Lꢀꢀke 2000 Research Program of TEKES, the National Technology Agency of Finland,
Hormos Medical Corp., Juvantia Pharma Ltd., Orion Pharma Corp., and the Finnish Work Environment
Fund for financial support.
Experimental Part
¨
General. Reagents were obtained from Aldrich, Fluka, Acros, and Riedel-de Haen. Wang resin
(polymer-bound 4-(benzyloxy)benzyl alcohol, loading 0.64 – 1.1 mmol/g; 100 – 200 or 200 – 400 mesh;
cross-linked with 1% divinylbenzene) was commercially available from NovaBiochem. The yields are
based on the actual loading of the commercial resin. The solvent 1,4-dioxane was dried by distilling over
Na, or dry 1,4-dioxane from Acros was used. Et3N was predried with CaSO4 and distilled over P2O5.
Otherwise, commercial-grade reagents and solvents were used without further purification or drying.
TLC: Merck aluminium sheets coated with silica gel 60 F254 (SiO2); visualization by UV at 254 nm.

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Helvetica Chimica Acta – Vol. 93 (2010)
Column chromatography (CC): Merck silica gel 60, SiO2; 230 – 400 mesh HPLC: Acquity-UPLC-BEH-
C18 column (1.7 mm, 2.1 ꢂ 50 mm; Waters), column oven set at 408; eluents 0.1% aq. HCO2H soln. and
MeCN, linear gradient 5 – 90% MeCN within 4 min; flow rate 1.0 ml/min. M.p.: Electrothermal-IA9100
digital melting-point apparatus; uncorrected. LC/UV Analyses: Waters Acquity UPLC instrument
equipped with an Acquity photodiode-array UV detector at 210 nm (40 scans/min). IR Spectra: Bruker-
Vertex-70 FT-IR spectrometer; KBr technique; n˜ in cmꢀ1. NMR Spectra: Varian-Mercury-300-Plus
spectrometer; in (D6)acetone; chemical shifts d in ppm rel. to Me4Si (¼0.00 ppm) in the 1H spectra
(300 MHz) and rel. to (D6)acetone (¼ 29.84 ppm) in the 13C spectra (75 MHz). GLC/MS: Hewlett-
Packard-HP-5890A gas chromatograph equipped with an HP-5970 mass-selective detector; capillary
column HP5-MS (12 m ꢂ 0.25 mm); carrier gas He; oven temp. program: 1008 (0 min), 208/min, 3108
(3 min); injection and detection temp. 250 and 2808, resp.; in m/z (rel. %). Elemental analyses:
Robertson Microlit Laboratories Inc., Madison, N. J.
Loading of Propargylamine to Wang Resin through a Carbamate Linker. Propargylamine was
attached to the Wang resin according to a reported procedure [26] suitable for primary and secondary
amines with minor modifications. Wang resin (polymer-bound 4-(benzyloxy)benzyl alcohol loading
0.64 – 1.1 mmol/g) was swelled in CH2Cl2 (12 ml/g resin). Pyridine (1.15 ml/g resin) was added, and then
4-nitrophenyl carbonochloridate (5 equiv.) in CH2Cl2 (7.5 ml/g). The mixture was stirred at r.t. for 2 h,
filtered, and washed with CH2Cl2 (5 ꢂ 5 ml/g resin). The resulting carbonate resin was added
immediately into the soln. of propargylamine (5 equiv.) in DMF (1:60; n/n) at 08. The mixture was
stirred at r.t. for 20 h. After filtering, the resin was washed twice (2 ꢂ 5 ml/g resin) each with DMF,
MeOH, THF, Et2O, and CH2Cl2, and dried in vacuo.
Sonogashira Coupling of Polymer-Bound Propargylamine with Aryl Iodides in Solution: General
Procedure 1 (G.P.1). Polymer-bound propargylamine (600 – 1000 mg, 0.64 – 1.1 mmol/g), aryl iodide (3 –
5 equiv.), and CuI (60 – 70 mg, 0.4 equiv.) were mixed with anh. 1,4-dioxane (10 ml) and anh. Et3N (5 ml)
under Ar. [Pd(PPh3)2]Cl2 (95 – 120 mg, 0.2 equiv.) was added under a gentle flow of Ar. The mixture was
stirred at r.t. for 20 – 73 h. After filtering, the resin was washed with 2 ꢂ 10 ml of each DMF, MeOH, THF,
Et2O, and CH2Cl2, and dried in vacuo.
Cleavage and Acetylation of the Coupling Product: General Procedure 2 (G.P.2) Polymer-bound
coupling product (600 – 800 mg) was stirred in CF3COOH/CH2Cl2 1:1 (5 ml) at r.t. for 2 h. After
filtering, the resin was washed successively with CH2Cl2 and MeOH. The filtrate was concentrated to give
the crude product which was dissolved in N,N-diisopropylethylamine (1 ml) and Ac2O (1 ml). A cat.
amount of DMAP was added, and the mixture was stirred at r.t. for 2 h. The solvents were evaporated
twice with EtOH (10 ml) to give the crude acetylated product, which was subjected to CC (SiO2).
N-(3-Phenylprop-2-yn-1-yl)acetamide. According to the G.P.1, with polymer-bound propargylamine
(806 mg, 1.1 mmol/g), iodobenzene (500 ml, 915 mg, 4.49 mmol), CuI (72.1 mg, 0.379 mmol), and
[Pd(PPh3)2]Cl2 (120 mg, 0.171 mmol) for 44 h. Cleavage (749 mg) and acetylation according to the G.P.2
followed by CC (SiO2, AcOEt/hexane 3 :1) gave the known [32] compound (57.8 mg, 41%). Pale yellow
solid. M.p. 72 – 738 ([24]: 78.2 – 79.48). Rf 0.41 (acetone/AcOEt 1:4). FT-IR: 695, 763, 1029, 1295, 1542,
1651, 3299. 1H-NMR: 1.93 (s, 3 H); 4.21 (d, J ¼ 5.4, 2 H); 7.32 – 7.42 (m, 5 H). 13C-NMR: 22.7; 29.7; 82.6;
87.2; 123.9; 129.1; 129.3; 132.3; 169.8. GLC/MS: 173, 158, 130 (100), 103.
N-[3-(4-Nitrophenyl)prop-2-yn-1-yl]acetamide. According to the G.P.1, with polymer-bound prop-
argylamine (804 mg, 1.1 mmol/g), 1-iodo-4-nitrobenzene (804 mg, 3.68 mmol), CuI (71.7 mg,
0.376 mmol), and [Pd(PPh3)2]Cl2 (123 mg, 0.175 mmol) for 44 h. Cleavage (755 mg) and acetylation
according to the G.P.2 followed by CC (SiO2, AcOEt) gave the product (93.8 mg, 52%). Yellow crystals.
1
M.p. 137 – 1388. Rf 0.38 (acetone/AcOEt 1:4). FT-IR: 687, 857, 1280, 1347, 1540, 1643, 3308. H-NMR:
1.95 (s, 3 H); 4.28 (d, J ¼ 5.1, 2 H); 7.66 (d, J ¼ 9.0, 2 H); 8.23 (d, J ¼ 9.0, 2 H). 13C-NMR: 22.7; 29.7; 80.9;
92.8; 124.5; 130.6; 133.4; 148.1; 169.9. GLC/MS: 218 (100), 203, 175, 129, 103. Anal. calc. for C11H11N2O3
(219.22): C 60.55, H 4.62, N 12.84; found: C 60.70, H 4.77, N 12.55.
N-[3-(4-Cyanophenyl)prop-2-yn-1-yl]acetamide. According to the G.P.1, with polymer-bound
propargylamine (823 mg, 1.1 mmol/g), 4-iodobenzonitrile (511 mg, 2.58 mmol), CuI (70.9 mg,
0.372 mmol), and [Pd(PPh3)2]Cl2 (120 mg, 0.171 mmol) for 72 h. Cleavage (749 mg) and acetylation
according to the G.P.2 followed by CC (SiO2, acetone/AcOEt 1:5) gave the product (97.7 mg, 60%).
Colorless crystals. M.p. 159 – 1618. Rf 0.38 (acetone/AcOEt 1:4). FT-IR: 677, 842, 1275, 1539, 1642, 2227,

Helvetica Chimica Acta – Vol. 93 (2010)
45
3308. 1H-NMR: 1.9 (s, 3 H); 4.25 (d, J ¼ 6.0, 2 H); 7.59 (d, J ¼ 8.7, 2 H); 7.77 (d, J ¼ 8.7, 2 H). 13C-NMR:
22.7; 29.7 81.1; 91.9; 112.5; 118.9; 128.7; 133.1; 169.8. GLC/MS: 198, 183, 155 (100). Anal. calc. for
C12H10N2O (198.22): C 72.71, H 5.08, N 14.13; found: C 71.63, H 4.96, N 13.37.
N-[3-(2-Chlorophenyl)prop-2-yn-1-yl]acetamide. According to the G.P.1, with polymer-bound
propargylamine (1006 mg, 0.74 mmol/g), 1-chloro-2-iodobenzene (460 ml, 898 mg, 4.32 mmol), CuI
(60.5 mg, 0.318 mmol), and [Pd(PPh3)2]Cl2 (108 mg, 0.154 mmol) for 18 h. Cleavage (815 mg) and
acetylation according to the G.P.2 followed by CC (SiO2, hexane/AcOEt 1:4) gave the product (68.3 mg,
55%). Yellow crystals. M.p. 106 – 1088. Rf 0.42 (acetone/AcOEt 1:4). FT-IR: 669, 758, 1063, 1278, 1544,
1633, 3294. 1H-NMR: 1.95 (s, 3 H); 4.28 (d, J ¼ 5.4, 2 H); 7.28 – 7.40 (m, 2 H); 7.45 – 7.52 (m, 2 H); 7.6 – 7.7
(br., NH). 13C-NMR: 22.7; 29.7; 76.2; 92.8; 123.5; 127.8; 130.1; 130.6; 134.4; 169.8. GLC/MS: 209, 207
(100), 166, 164, 130, 101. Anal. calc. for C11H10ClNO (207.66): C 63.62, H 4.85, N 6.75; found: C 63.53, H
5.08, N 6.55.
N-[3-(3-Bromophenyl)prop-2-yn-1-yl]acetamide. According to the G.P.1, with polymer-bound
propargylamine (815 mg, 1.1 mmol/g), 1-bromo-3-iodobenzene (340 ml, 754 mg, 2.67 mmol), CuI
(77.8 mg, 0.409 mmol), and [Pd(PPh3)2]Cl2 (120 mg, 0.171 mmol) for 22 h. Cleavage (770 mg) and
acetylation according to the G.P.2 followed by CC (SiO2, AcOEt, acetone/AcOEt 1:5) gave the product
(117 mg, 55%). Yellow crystals. M.p. 89 – 918. Rf 0.42 (acetone/AcOEt 1:4). FT-IR: 678, 773, 1242, 1294,
1558, 1636, 3065, 3249. 1H-NMR: 1.93 (s, 3 H); 4.21 (d, J ¼ 5.7, 2 H); 7.28 – 7.42 (m, 3 H); 7.52 – 7.57 (m,
1 H). 13C-NMR: 22.7; 29.6; 80.9; 89.0; 122.6; 126.1; 131.18; 131.25; 132.3; 134.8; 169.8. GLC/MS: 253, 251,
238, 236, 210, 208 (100), 130, 102, 75. Anal. calc. for C11H10BrNO (252.11): C 52.41, H 4.00, N 5.56; found:
C 52.17, H 3.79, N 5.28.
N-[3-(3-Formylphenyl)prop-2-yn-1-yl]acetamide. According to the G.P.1, with polymer-bound
propargylamine (808 mg, 1.1 mmol/g), 3-iodobenzaldehyde (633 mg, 2.73 mmol), CuI (72.4 mg,
0.380 mmol), and [Pd(PPh3)2]Cl2 (120 mg, 0.171 mmol) for 22 h. After cleavage (777 mg) according to
the G.P.2, and concentration, the residue was cooled to ꢀ 1008 in a liq. N2/EtOH bath, and Ac2O (1.0 ml),
N,N-diisopropylethylamine (1.0 ml), and a cat. amount of DMAP were added. The mixture was stirred in
the cooling bath from ꢀ 1008 to r.t. for 22 h. After evaporation with EtOH (2 ꢂ 10 ml), the residue was
subjected to CC (SiO2, hexane/AcOEt 1:2, AcOEt, acetone/AcOEt 1:10) gradient to give the product
(76.1 mg, 44%). Red-brown oil. Rf 0.37 (acetone/AcOEt 1:4). FT-IR: 685, 1160, 1282, 1542, 1656, 1700,
3063, 3281. 1H-NMR: 1.9 (s, 3 H); 4.25 (d, J ¼ 5.4, 2 H); 7.54 – 7.74 (m, 3 H); 7.87 – 7.93 (m, 1 H); 10.0 (s,
1 H). 13C-NMR: 22.7; 29.7; 81.3; 88.8; 124.9; 129.7; 130.3; 133.2; 137.6; 137.8; 170.0; 192.4. GLC/MS: 201
(100), 186, 158, 130, 77. Anal. calc. for C12H11NO2 (201.22): C 71.63, H 5.51, N 6.96; found: C 69.22, H 5.08,
N 6.36.
N-[3-(4-Fluorophenyl)prop-2-yn-1-yl]acetamide. According to the G.P.1, with polymer-bound
propargylamine (811 mg, 1.1 mmol/g), 1-fluoro-4-iodobenzene (510 ml, 982 mg, 4.42 mmol), CuI
(69.6 mg, 0.365 mmol), and [Pd(PPh3)2]Cl2 (120 mg, 0.171 mmol) for 24 h. Cleavage (762 mg) and
acetylation according to the G.P.2 followed by CC (SiO2, AcOEt) gave the product (24.1 mg, 15%). Pale
yellow crystals. M.p. 1058. Rf 0.41 (acetone/AcOEt 1:4). FT-IR: 728, 817, 817, 840, 1094, 1221, 1507, 1547,
1646, 3296. 1H-NMR: 1.91 (s, 3 H); 4.18 (d, J ¼ 5.4, 2 H); 7.09 – 7.18 (m, 2 H); 7.42 – 7.49 (m, 2 H).
13C-NMR (o, m, p, ipso with respect to F): 22.7; 29.5; 81.4; 87.0; 116.5 (d, 2J(Co,F) ¼ 22.2); 120.3 (d,
4J(Cp,F) ¼ 3.4); 134.5 (d, 3J(Cm,F) ¼ 8.3); 163.3 (d, 1J(Cipso,F) ¼ 245.9); 169.7. GLC/MS: 191, 176, 148
(100), 133. Anal. calc. for C11H10FNO (191.20): C 69.10, H 5.27, N 7.33; found: C 67.44, H 4.56, N 6.95.
N-[3-(Pyridin-3-yl)prop-2-yn-1-yl]acetamide. According to the G.P.1, with polymer-bound prop-
argylamine (804 mg, 1.1 mmol/g), 3-iodopyridine (547 mg, 2.67 mmol), CuI (85.5 mg, 0.449 mmol), and
[Pd(PPh3)2]Cl2 (121 mg, 0.172 mmol) for 22 h. Cleavage (762 mg) and acetylation according to the G.P.2
followed by CC (SiO2, acetone/AcOEt 1:2) gave the product (67.6 mg, 47%). Dark red oil. Rf 0.19
(acetone/AcOEt 1:4). FT-IR: 705, 1286, 1409, 1545, 1657, 3057, 3266. 1H-NMR: 1.95 (s, 3 H); 4.25 (d, J ¼
5.4, 2 H); 7.37 (ddd, J ¼ 0.9, 4.8, 7.8, 1 H); 7.78 (td, J ¼ 1.8, 8.1, 1 H); 8.54 (dd, J ¼ 1.7, 5.0, 1 H); 8.59 (d, J ¼
1.5, 1 H). 13C-NMR: 22.7; 29.7; 79.4; 90.7; 120.8; 124.1; 139.2; 149.6; 152.8; 169.9. GLC/MS: 174, 159, 131
(100), 105, 104, 79. Anal. calc. for C10H10N2O (174.20): C 68.95, H 5.79, N 16.08; found: C 66.00, H 5.88, N
14.78.
N-[3-(3-Chlorophenyl)prop-2-yn-1-yl]acetamide. According to the G.P.1, with polymer-bound
propargylamine (806 mg, 1.1 mmol/g), 1-chloro-3-iodobenzene (550 ml, 1060 mg, 4.45 mmol), CuI

46
Helvetica Chimica Acta – Vol. 93 (2010)
(69.7 mg, 0.366 mmol), and [Pd(PPh3)2]Cl2 (122 mg, 0.172 mmol) for 22 h. Cleavage (806 mg) and
acetylation according to the G.P.2 followed by CC (SiO2, AcOEt) gave the product (93.0 mg, 51%). Pale
yellow crystals. M.p. 84 – 858. Rf 0.36 (acetone/AcOEt 1:4). FT-IR: 679, 776, 1097, 1240, 1295, 1562, 1634,
3066, 3249. 1H-NMR: 1.93 (s, 3 H); 4.21 (d, J ¼ 5.7, 2 H); 7.34 – 7.44 (m, 4 H). 13C-NMR: 22.7; 29.5; 81.0;
88.9; 125.8; 129.4; 130.8; 130.8; 131.1; 131.9; 134.6; 169.7. GLC/MS: 209, 207, 194, 192, 166, 164 (100), 130,
102. Anal. calc. for C11H10ClNO (207.66): C 63.62, H 4.85, N 6.75; found: C 63.35, H 5.13, N 6.48.
N-[3-(4-Chlorophenyl)prop-2-yn-1-yl]acetamide. According to the G.P.1, with polymer-bound
propargylamine (814 mg, 1.1 mmol/g), 1-chloro-4-iodobenzene (1076 mg, 4.51 mmol), CuI (73.0 mg,
0.383 mmol), and [Pd(PPh3)2]Cl2 (122 mg, 0.172 mmol) for 22 h. Cleavage (814 mg) and acetylation
according to the G.P.2 followed by CC (SiO2, AcOEt) gave the product (67.8 mg, 36%). Pale yellow
solid. M.p. 128 – 1308. Rf 0.35 (acetone/AcOEt 1:4). FT-IR: 619, 750, 828, 1089, 1250, 1296, 1634, 2854,
2922, 3254. 1H-NMR: 1.92 (s, 3 H); 4.20 (d, J ¼ 5.1, 2 H); 7.36 – 7.46 (m, 4 H). 13C-NMR: 22.7; 29.6; 81.3;
88.5; 122.7; 129.6; 133.9; 134.6; 169.7. GLC/MS: 209, 207, 194, 192, 166, 164 (100), 149, 130, 113, 102. Anal.
calc. for C11H10ClNO (207.66): C 63.62, H 4.85, N 6.75; found: C 63.84, H 5.41, N 6.23.
N-[3-(3-Methoxyphenyl)prop-2-yn-1-yl]acetamide. According to the G.P.1, with polymer-bound
propargylamine (804 mg, 1.1 mmol/g), 1-iodo-3-methoxybenzene (530 ml, 1040 mg, 4.44 mmol), CuI
(71.4 mg, 0.375 mmol), and [Pd(PPh3)2]Cl2 (118 mg, 0.168 mmol) for 21 h. Cleavage (804 mg) and
acetylation according to the G.P.2 followed by CC (SiO2, AcOEt) gave the product (56 mg, purity by LC/
UV 79%, i.e., 44 mg of pure product, 24%). Brown yellow oil. Rf 0.36 (acetone/AcOEt 1:4). FT-IR:
1041, 1203, 1288, 1655, 2932, 3279. 1H-NMR: 1.92 (s, 3 H); 3.80 (s, 3 H); 4.19 (d, J ¼ 5.4, 2 H); 6.85 – 7.03
(m, 3 H); 7.16 – 7.31 (m, 1 H). 13C-NMR: 22.7; 29.6 (overlapped with (D6)acetone); 55.6; 82.5; 87.0;
115.5; 117.2; 122.4; 124.7; 130.42; 130.44; 160.5. GLC/MS: 203 (100), 202, 188, 160, 145, 130. Anal. calc.
for C12H13NO2 (203.24): C 70.92, H 6.45, N 6.89; found: C 69.27, H 6.68, N 4.80.
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Received April 15, 2009