Efficient synthesis of alkynyl amides via aminocarbonylation of iodoalkynes

Article abstract of DOI:10.1016/j.tet.2018.09.001

Iodoethynylbenzene as iodoalkyne model compound was aminocarbonylated with tert-butylamine under carbon monoxide atmosphere in the presence of in situ palladium(0) catalysts. The formation of the unsaturated carboxamide (alkynyl amide) is always accompanied by that of the Glaser coupling product, diphenylbutadiyne. The yield of the amide-forming reaction was optimised by the systematic variation of the phosphine ligand, carbon monoxide pressure and temperature. The scope of the reaction was investigated by using various primary and secondary amines including amino acid methyl esters as N-nucleophiles. 17α-(Iodoethynyl)-testosterone was also functionalised by using this methodology providing the corresponding 17α-(carboxamidoethynyl)-testosterone derivatives in up to 96% yields. The reaction was extended to 1-(iodoethynyl)cyclohex-1-ene and 1-iodohex-1-yne. Ethyl iodopropiolate gave the enamine type product by the addition of amine to the alkyne functionality which was formed from the iodoalkyne via deiodination under standard aminocarbonylation conditions. The bromo analogue, bromoethynylbenzene has shown lower reactivity than the corresponding iodo derivative.

Full text of DOI:10.1016/j.tet.2018.09.001

Accepted Manuscript
Efficient synthesis of alkynyl amides via aminocarbonylation of iodoalkynes
Péter Szuroczki, Borbála Boros, László Kollár
PII:
S0040-4020(18)31054-8
10.1016/j.tet.2018.09.001
TET 29773
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 May 2018
Revised Date: 29 August 2018
Accepted Date: 1 September 2018
Please cite this article as: Szuroczki Pé, Boros Borbá, Kollár Láó, Efficient synthesis of alkynyl amides
via aminocarbonylation of iodoalkynes, Tetrahedron (2018), doi: 10.1016/j.tet.2018.09.001.
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ACCEPTED MANUSCRIPT
Efficient Synthesis of Alkynyl Amides via Aminocarbonylation of Iodoalkynes
P. Szuroczki, B. Boros and L. Kollár
Graphical abstract

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ACCEPTED MANUSCRIPT
Efficient Synthesis of Alkynyl Amides via Aminocarbonylation of Iodoalkynes
Péter Szuroczki,a Borbála Borosb and László Kollára,c,*
a) Department of Inorganic Chemistry, University of Pécs and Szentágothai Research Centre, H-7624
Pécs, P.O. Box 266, Hungary; e-mail: kollar@gamma.ttk.pte.hu
b) Department of Analytical and Environmental Chemistry, University of Pécs, H-7624 Pécs, Ifjúság u.
6., Hungary
c) MTA-PTE Research Group for Selective Chemical Syntheses, H-7624 Pécs, Ifjúság u. 6., Hungary
Abstract: Iodoethynylbenzene as iodoalkyne model compound was aminocarbonylated
with tert-butylamine under carbon monoxide atmosphere in the presence of in situ
palladium(0) catalysts. The formation of the unsaturated carboxamide (alkynyl amide)
is always accompanied by that of the Glaser coupling product, diphenylbutadiyne. The
yield of the amide-forming reaction was optimized by the systematic variation of the
phosphine ligand, carbon monoxide pressure and temperature. The scope of the
reaction was investigated by using various primary and secondary amines including
amino acid methyl esters as N-nucleophiles.
17α-(Iodoethynyl)-testosterone was also functionalised by using this methodology
providing the corresponding 17α-(carboxamidoethynyl)-testosterone derivatives in up
to 96% yields. The reaction was extended to 1-(iodoethynyl)cyclohex-1-ene and 1-
iodohex-1-yne. Ethyl iodopropiolate gave the enamine type product by the addition of
amine to the alkyne functionality which was formed from the iodoalkyne via
deiodination under standard aminocarbonylation conditions. The bromo analogue,
bromoethynylbenzene has shown lower reactivity than the corresponding iodo
derivative.
Key-words: iodoalkyne, palladium, carbon monoxide, aminocarbonylation, carboxamide

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Introduction
Carboxamides are among the most investigated compounds with high synthetic significance discussed
even in fundamental text-books.1 The conventional carboxylic acid–acyl halide–carboxamide route can be
circumvented by homogeneous catalytic methodologies which are based on finding applications in various
types of transition metal catalysed reactions.2 As a real breakthrough, the discovery of palladium-catalysed
aminocarbonylation of haloaromatics (iodoarenes and bromoarenes) and that of their synthetic surrogates, aryl
triflates, lead to the great variety of aromatic carboxamides.3 Similarly, the reaction of iodoalkenes and their
analogues, enoltriflates, provided the corresponding α,β-unsaturated carboxamides. The palladium-catalysed
aminocarbonylation of both types of substrates was reviewed in many book-chapters and journal reviews.4
Although carboxamides, possessing carboxamido functionality attached to an sp2-carbon, were
synthesised in great variety, far less examples are known for the synthesis of carboxamides containing an sp-
carbon—amide bond. As an obvious strategy, haloalkyne-based carbonylation reactions can be used. A
halodecarboxylation protocol was reported for the synthesis of haloalkynes by using substituted propiolic
acids.5 N-Iodosuccinimide (NIS) was used for the synthesis of 17α-iodoethynyl-steroids.6
Arylalkynyl bromides were aminocarbonylated under mild conditions toward the corresponding
carboxamides in the presence of dicobalt octacarbonyl as a CO source.7 Alkynyl amides were synthesized in a
palladium-catalyzed coupling reaction of alkynyl carboxylic acids and amines under carbon monoxide via
decarboxylation of the substrate.8 Propiolamides were synthesised via carbamoylation in the presence of
copper catalysts.9 Terminal alkynes were trasnsferred to the corresponding carboxamides via oxidative
aminocarbonylation using Pd/C catalyst.10 Aryl-substituted propiolamides were synthesised from
iodopropiolamides and arylboronic acids via Suzuki-Miyaura reaction.11
Hypervalent iodine(III) reagents/photoredox dual catalysis were used for the synthesis of alkynyl amide
via radical ynonylation.12 N-Aryl-substituted alkynyl amide underwent palladium-catalyzed domino
carbopalladation/C-H activation/C-C bond-formation.13 N,N-Disubstituted alkynyl amides were reacted with
isolated diynes to yield benzamides with axial chirality in highly enantioselective cyclization reaction.14
Alkynyl amides represent an important family of unsaturated carboxamides due to their
pharmacological importance.15 Encouraged by their application as building blocks even in further transition
metal catalysed reactions, we extended our systematic investigations in the field of carbonylation reactions to
the investigation of iodoalkynes. This way, the high-yielding aminocarbonylation of iodoalkynes with various
primary and secondary amines is reported here.

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Results and Discussion
Synthesis of iodoalkynes (2, 4, 6, 8 and 10)
For the synthesis of iodoalkynyl substrates, applicable in further catalytic transformations, terminal
alkynes such as ethynylbenzene (1), 17α-(ethynyl)-testosterone (3), 1-ethynylcyclohex-1-ene (5), 1-hexyne (7)
and ethyl propiolate (9) were chosen as starting material. The non-functionalised iodoalkynes,
iodoethynylbenzene (2) and 1-iodohex-1-yne (8) were obtained by direct iodination in the presence of
iodomorpholinium iodide formed in situ from morpholine and iodine.16 The three additional functionalised
iodoalkynes, 7α-(iodoethynyl)-testosterone (4), 1-(iodoethynyl)cyclohexene (6) and ethyl iodopropiolate (10)
were obtained in excellent yields by using N-iodosuccinimide (NIS) as iodination agent (Scheme 1).4a The
bromoalkyne derivative (2’) was synthesised according to a similar methodology by using N-
bromosuccinimide (NBS) as bromination agent.6
Scheme 1. Synthesis of iodoalkynes (2, 4, 6, 8 and 10) and bromoalkyne (2’) used as substrates in
aminocarbonylations

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Aminocarbonylation of iodoalkyne (2) and bromoalkyne (2’)
Iodoethynylbenzene (2) was reacted with tert-butylamine (a) and carbon monoxide under various
conditions. Highly reactive palladium(0) catalysts, formed in situ from palladium(II) acetate and the
appropriate monodentate (PPh3, PtBu3, PCy3, P(OPh)3) or bidentate P-ligands (dppe, dppp, dppf, Xantphos),
were used. The in situ reduction of Pd(II) to Pd(0) resulting in low-ligated, highly active palladium complexes
was discussed previously.17
The formation of the target alkynyl amide (11a) is accompanied by that of the Glaser-coupling
derivative, diphenylbutadiyne (12) (Table 1). Although the two products are formed in comparable amounts
under atmospheric pressure, the chemoselectivity toward 11a can be substantially increased by using higher
CO pressures (entries 3 and 4). Higher temperatures favour direct coupling (the formation of 12) at
atmospheric pressure, i.e., lower chemoselectivity toward 11a was obtained (compare entries 2, 5 and 6). It
has to be noted, that no similar effect was observed at high pressure. Similar 11a/12 ratios were obtained at 80
bar CO pressure at different temperatures (entries 4 and 7).
A similar effect of the pressure was observed using phosphines of high basicity, i.e., in the presence of
PBu3 the higher CO pressure favours higher chemoselectivity towards amide (entries 9 and 10). A typical
chemoselectivity of ca. 80% was observed also with PCy3 (entry 8). The flexible diphosphines
(Ph2P(CH2)nPPh2) gave much lower chemoselectivities (entries 11-13). The rigid diphosphines, dppf and
Xantphos, especially, provided 11a/12 ratios similar to those obtained with monodentate ligands (entries 14
and 15). It is worth noting that even in case of Xantphos ligand the increase of the temperature resulted in
similar chemoselectivity as with PPh3 (compare entries 5 and 16). The tested phosphite ligand (P(OPh)3) also
formed active catalytic system with palladium, providing carboxamide yields similar to basic monodentate
ligands (entry 17).
The bromoalkyne derivative (2’) shows much lower reactivity than the corresponding iodoalkyne
substrate (2). Higher temperature and elevated reaction times are necessary to achieve conversions similar to 2
(entry 18).

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Table 1. Aminocarbonylation of iodoethynylbenzene (2) in the presence of tert-butylamine as N-
nucleophile (optimization of the reaction conditions)a
Ligand
T
Ratio of Yielde
Entry
p(CO) R.time
11a/12b
(11a)
[%]
n.i.
62
[oC] [bar]
[h]
2.5
20
2.5
2.5
2
PPh3
PPh3
25
25
25
25
50
70
70
25
25
25
25
25
25
25
25
50
25
50
1
1
50/50c
70/30
91/9
1
2
PPh3
40
80
1
85
3
PPh3
88/12
52/48
29/71
89/11
79/21
70/30
82/18
62/38d
61/39
53/47
80/20
92/8
68
4
PPh3
45
5
PPh3
1
1
10
6
PPh3
80
40
1
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1
68
7
P(Cy)3
PtBu3
PtBu3
dppe
75
8
35
9
40
40
40
40
40
40
1
20
10
11
12
13
14
15
16
17
18f
n.i.
60
dppe
dppp
48
dppf
74
Xantphos
Xantphos
P(OPh)3
PPh3
82
48/52
83/17
70/30
n.i.
76
40
1
2.5
8
n.i.
a) Reaction conditions: 1 mmol of substrate (2), 2 mmol of tert-butylamine nucleophile (a); 0.025 mmol of
Pd(OAc)2, 0.05 mmol monophosphine or P(OPh)3, (or 0.025 mmol of diphosphine); 0.5 mL of Et3N, 10 ml of
DMF
b) Determined by GC and GC–MS. Conversion of 97-99% was achieved in all cases (unless otherwise stated).
c) Conversion: 42%
d) Conversion: 73%
e) Isolated yield based on the starting amount of the substrate (2)
f) 2’ was used as substrate
Aminocarbonylation of iodoalkynes using various N-nucleophiles
o
Iodoalkynes 2 and 4 were aminocarbonylated under optimised reaction conditions (40 bar CO, 25 C)
(Table 2 and Table 3, respectively). In addition to the tert-butylamine (a) discussed above, piperidine (b),
morpholine (c), allylamine (d), methyl glycinate (e), methyl alaninate (f), methyl valinate (g), methyl prolinate

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(h), methyl phenylalaninate (i), N,O-dimethylhydroxylamine (j) and (S)-2-methylbenzylamine (k) were used as
N-nucleophile. Both substrates were practically fully converted to the carboxamides (11a-k and 13a-k,
respectively). Considering the whole range of amines (a-k) good to excellent yields (up to 96%) for the
isolated carboxamides were obtained. Nucleophiles d and i gave the lowest isolated yields in both series of
carboxamides (entries 4 and 9 in both Tables) due to difficulties in chromatographic separation. It has to be
noted that the corresponding carboxamides were formed in high yields even in these cases based on the NMR
analysis of the crude reaction products.
Table 2. Aminocarbonylation of 2 in the presence of various primary and secondary aminesa
Entry
Amine
R'
tBu
(CH2)5
Yieldb
[%]
R
H
85 (11a)
84 (11b)
81 (11c)
62 (11d)
67 (11e)
80 (11f)
75 (11g)
83 (11h)
59 (11i)
63 (11j)
96 (11k)
1
2
(CH2)2O(CH2)2
CH2CH=CH2
3
H
H
H
H
4
CH2COOCH3
5
CH(CH3)COOCH3
CH(CH(CH3)2)COOCH3
CH(COOCH3)(CH2)3
CH(CH2Ph)COOCH3
OCH3
6
7
8
H
CH3
H
9
10
11
(S)-CH(CH3)Ph
a) Reaction conditions: 1 mmol of substrate, 2 mmol of amine nucleophile (a-k); 0.025 mmol of Pd(OAc)2,
0.05 mmol of PPh3, 0.5 mL of Et3N, 10 ml of DMF, 40 bar CO, 25 oC.
b) Yield of the isolated product based on the starting amount of the substrate (2).

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Table 3. Aminocarbonylation of 4 in the presence of various primary and secondary amines (for
reaction conditions see Table 2)
Entry
Amine
R'
tBu
(CH2)5
Yield
R
H
[%]
95 (13a)
96 (13b)
96 (13c)
65 (13d)
92 (13e)
90 (13f)
60 (13g)
65 (13h)
56 (13i)
75 (13j)
78 (13k)
1
2
(CH2)2O(CH2)2
CH2CH=CH2
3
H
H
H
H
4
CH2COOCH3
5
CH(CH3)COOCH3
CH(CH(CH3)2)COOCH3
CH(COOCH3)(CH2)3
CH(CH2Ph)COOCH3
OCH3
6
7
8
H
CH3
H
9
10
11
(S)-CH(CH3)Ph
To investigate the scope of the substrates in aminocarbonylation, 6 and 8 were aminocarbonylated using
selected amines (a-c, e, f, j) (Table 4 and 5, respectively). The alkynyl amides were isolated in analytical purity
and fully characterised in both cases. Moderate isolated yields were obtained. As above, it is worth noting that
the relatively low yields are due to the loss of the products during isolation with column chromatography. The
only side-product the Glaser-coupled diyne was formed in less than 3%. The diynes were even not detectable
in the reaction mixture (isolated as crude products still containing the catalyst, ammonium salts and side-
products, if any) with NMR. Excellent yields were obtained with nucleophiles c and f (Table 5, entries 3 and
5).

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Table 4. Aminocarbonylation of 6 in the presence of various primary and secondary amines (for
reaction conditions see Table 2)
Entry
Amine
R'
tBu
(CH2)5
Yield
[%]
R
H
53 (14a)
59 (14b)
55 (14c)
59 (14e)
47 (14f)
35 (14j)
1
2
3
4
5
6
(CH2)2O(CH2)2
CH2COOCH3
CH(CH3)COOCH3
OCH3
H
H
CH3
Table 5. Aminocarbonylation of 8 in the presence of various primary and secondary amines (for
reaction conditions see Table 2)
Entry
Amine
R'
tBu
(CH2)5
Yieldb
[%]
R
H
56 (15a)
64 (15b)
95 (15c)
53 (15e)
86 (15f)
52 (15j)
1
2
3
4
5
6
(CH2)2O(CH2)2
CH2COOCH3
CH(CH3)COOCH3
OCH3
H
H
CH3
The third type of iodoalkyne, the activated ethyl iodopropiolate (10) gave the enamine type product (16)
exclusively (Scheme 2) The loss of iodine from 10 resulting in ethyl propiolate took place under the reductive
conditions used and was followed by the addition of amine to the alkyne functionality. Since no similar
reaction(s) were detected, the following reaction sequence could be suggested in order to rationalize the
formation of 16. tert-Butylamine could serve as a hydrogen source for the hydrogenolysis of the iodoalkyne

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moiety while corresponding hydrazines and ammonium iodides are formed. The addition of the amine (a) to
the activated triple bond brings about enamine (16). As a consequence of the above preferred side-reactions the
target alkynyl amide was formed only in traces (less than 1%) and was detected by GC-MS only.
Scheme 2. Reactions of 10 under aminocarbonylation conditions (formation of enamines accompanied by
deiodination)
Conclusions
Iodoalkynes, easily accessible from alkynes, can be considered as appropriate starting materials for the
synthesis of alkynyl amides. Under mild conditions the iodoalkyne substrate undergoes aminocabonylation
reaction in the presence of carbon monoxide and primary and secondary amines. The amount of the most
characteristic side product, the Glaser coupling derivative can be substantially reduced by the optimization of
the reaction conditions (systematic variation of the phosphine ligand, carbon monoxide pressure and
temperature).
Experimental
3.1. General procedures
13
1H and C NMR spectra were recorded in CDCl3 on a Bruker Avance III 500 spectrometer at 500 and
125.7 MHz, respectively. Chemical shifts δ are reported in ppm relative to residual CHCl3 (7.26 and 77.00
1
ppm for H and 13C, respectively). The FT-IR spectra were taken in KBr pellets using an IMPACT 400
spectrometer (Nicolet) applying a DTGS detector in the region of 400-4000 cm-1,the resolution was 4 cm-1.
MS measurements were carried out on an Agilent LC-MSD-TRAP-XCT apparatus in ESI (positive) mode.
Samples of the catalytic reactions were analysed with a Hewlett Packard 5830A gas chromatograph fitted with
a capillary column coated with OV-1.
The alkynes and N-nucleophiles were purchased from Sigma-Aldrich and were used without further
purification. 2-Bromophenylacetylene (2’) substrate was synthesised according to a known procedure.6
(Caution! 2-Bromophenylacetylene is a strong lacrimator (tear-producing compound).)
3.2. Aminocarbonylation experiments at normal pressure

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In a typical experiment a solution of Pd(OAc)2 (5.6 mg, 0.025 mmol), PPh3 (13.1 mg, 0.05 mmol) (or
PtBu3 HBF4 (14.5 mg, 0.05 mmol)), 1.0 mmol iodoethynylbenzene (2), 2.0 mmol tert-butylamine (a) were
dissolved in 10 mL of DMF under argon. Triethylamine (0.5 mL) was added to the homogeneous yellow
solution and the atmosphere was changed to carbon monoxide. The colour changed to dark red. The reaction
was conducted for 24 hours at 25, 50 or 70 oC. Some metallic palladium was formed at the end of the reaction
which was filtered off. (A sample of this solution was immediately analysed by GC-MS.) The mixture was
then concentrated and evaporated to dryness. The residue was dissolved in chloroform (20 mL) and washed
with water (20 mL). The organic phase was thoroughly washed twice with brine (20 mL), dried over Na2SO4
and concentrated to a red waxy material or a thick oil. Chromatography (silica, chloroform/hexane,
chloroform/ethyl acetate) yielded the desired compounds as pale yellow solid.
3.3. Aminocarbonylation experiments at high pressure
The DMF solution (10 mL) of the catalyst precursor (Pd(OAc)2 (5.6 mg, 0.025 mmol), 0.05 mmol
monophosphine or P(OPh)3, or 0.025 mmol of diphosphine) and the reactants (1.0 mmol of 2 or 0.5 mmol of 4
iodoalkyne substrate and 2 equivalents of N-nucleophile) and triethylamine (0.5 mL) was transferred under
argon into a 100 mL stainless steel autoclave. The reaction vessel was pressurised up to 40 or 80 bar total
pressure with carbon monoxide and the magnetically stirred mixture was heated in an oil bath at 50 or 70 oC or
stirred at room temperature for 2.5 h. The work-up procedure is identical with that given above.
3.4. Characterization of the products
N-(tert-Butyl)-3-phenylpropiolamide (11a): Yield: 171 mg (85%); pale yellow solid material, mp. 76-
77°C; Rf (5% EtOAc, 95% CHCl3) 0.88; δH (500 MHz, CDCl3) 7.54 (2H, d, J=7.2 Hz, Ar), 7.44-7.41 (1H, m,
Ar), 7.38-7.35 (2H, m, Ar), 5.77 (1H, brs, NH), 1.44 (9H, s, C(CH3)3 ). δC (125.7 MHz, CDCl3) 152.5, 132.4,
129.8, 128.5, 120.5, 84.1, 82.5, 52.4, 28.7. IR (KBr, ν (cm-1)): 3229 ν(NH), 3054 ν(CH, Ar), 2991, 2986, 2931,
2866 ν(CH3), 2220 ν(C≡C), 1625 Amide I., 1551 Amide II., 757 γ(=CH). MS m/z (rel int.): 201 (14, M+), 186
(25), 146 (16), 129 (100), 101 (8), 75 (13), 51 (5).
(3-Phenyl-propiolyl)-piperidine (11b): Yield: 179 mg (84%); off-white solid material, mp. 105 °C; Rf
(5% EtOAc, 95% CHCl3) 0.70; δH (500 MHz, CDCl3) 7.58-7.56 (2H, m, Ar), 7.45-7.42 (1H, m, Ar), 7.40-7.37
(2H, m, Ar), 3.81-3.79 (2H, m), 3.66-3.64 (2H, m), 1.74-1.59 (6H, m). δC (125.7 MHz, CDCl3) 153.0, 132.3,
129.9, 128.5, 120.8, 90.3, 81.5, 48.2, 42.4, 26.5, 25.4, 24.6. IR (KBr, ν (cm-1)): 2996, 2980, 2944 ν(CH2), 2215
ν(C≡C), 1623 Amide I., 1488, 1464, 1456, 1438 ν(C=C), 765 γ(=CH). MS m/z (rel int.): 213 (46, M+), 212
(50, M-1+), 184 (26), 156 (10), 129 (100), 101 (13), 75 (18), 56 (6), 51 (8).
4-(3-Phenylpropiolyl)-morpholine (11c): Yield: 174 mg (81%); off-white solid material, mp. 58-59 °C;
Rf (5% EtOAc, 95% CHCl3) 0.42; δH (500 MHz, CDCl3) 7.58-7.56 (2H, m, Ar), 7.47-7.43 (1H, m, Ar), 7.41-

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7.38 (2H, m, Ar), 3.88-3.86 (2H, m), 3.78-3.76 (2H, m), 3.73 (4H, s). δC (125.7 MHz, CDCl3) 153.2, 132.4,
130.2, 128.6, 120.3, 91.2, 80.8, 66.9, 66.5, 47.3, 42.0. IR (KBr, ν (cm-1)): 3057, 3045 ν(CH, Ar), 2973, 2923,
2898, 2862 ν(CH2), 2217 ν(C≡C), 1620 Amide I., 1493, 1453, 1444, 1433 ν(C=C), 1111 ν(C-O-C), 766
γ(=CH). MS m/z (rel int.): 215 (29, M+), 186 (12), 156 (10), 129 (100), 101 (11), 86 (18), 75 (19), 56 (18), 51
(7).
N-Allyl-3-phenylpropiolamide (11d): Yield: 115 mg (62%); yellow solid material, mp. 39-40 °C; Rf (5%
EtOAc, 95% CHCl3) 0.71; δH (500 MHz, CDCl3) 7.57-7.53 (2H, m, Ar), 7.45-7.40 (1H, m, Ar), 7.38-7.35
(2H, m, Ar), 6.19 (1H, brs, NH), 5.89 (1H, ddd, J= 15.9 Hz, 10.7 Hz, 5.7 Hz, CH=CH2), 5.28(1H, d, J= 15.9
Hz, CH=CH2(E)), 5.25 (1H, d, J= 10.7 Hz, CH=CH2(Z)), 3.99. δC (125.7 MHz, CDCl3) 153.3, 133.2, 132.5,
130.1, 128.5, 120.2, 117.1, 84.9, 82.9, 42.9. IR (KBr, ν (cm-1)): 3282 ν(NH), 3079, 3066, 3053, 3012 ν(CH,
Ar), 2980, 2920 ν(CH2), 2222 ν(C≡C), 1637 Amide I., 1534 Amide II, 1483, 1443, 1413 ν(C=C), 759 γ(=CH).
MS m/z (rel int.): 184 (21, M+), 156 (46), 142 (15), 129 (100), 101 (13), 75 (22), 51 (8).
Methyl N-(3-phenyl-propiolyl)-glycinate (11e): Yield: 145 mg (67%); pale yellow solid material, mp. 95-
96 °C; Rf (5% EtOAc, 95% CHCl3) 0.48; δH (500 MHz, CDCl3) 7.58-7.56 (2H, m, Ar), 7.47-7.44 (1H, m, Ar),
7.41-7.38 (2H, m, Ar), 6.54 (1H, brs, NH), 4.19 (2H, d, J= 5.2 Hz), 3.82 (3H, s, CH3). δC (125.7 MHz, CDCl3)
169.7, 153.3, 132.6, 130.3, 128.6, 120.0, 85.8, 82.4, 52.6, 41.5. (KBr, ν (cm-1)): 3274 ν(NH), 3063, 2993
ν(CH, Ar), 2949, 2954, 2819, 2756 ν(CH2, CH3), 2233 ν(C≡C), 1733 ν(C=O ester) 1626 Amide I., 1549 Amide
II., 1446, 1433 ν(C=C), 1285 ν(C-O-C ester), 764 γ(=CH). MS m/z (rel int.): 217 (13, M+), 158 (20), 129
(100), 101 (9), 75 (15), 51 (5).
Methyl N-(3-phenyl-propiolyl)-alaninate (11f): Yield: 185 mg (80%); viscous orange material; Rf (5%
EtOAc, 95% CHCl3) 0.68; δH (500 MHz, CDCl3) 7.57-7.55 (2H, m, Ar), 7.46-7.43 (1H, m, Ar), 7.40-7.36
(2H, m, Ar), 6.63 (1H, d, J= 5.7 Hz, NH), 4.75-4.69 (1H, m, CH), 3.81 (3H, s, CH3), 1.50 (3H, d, J= 7.2 Hz,
CH3). δC (125.7 MHz, CDCl3) 172.8, 152.7, 132.6, 130.2, 128.5, 120.1, 85.4, 82.7, 52.7, 48.3, 18.4. (KBr, ν
(cm-1)): 3259 ν(NH), 3057 ν(CH, Ar), 2952, 2876, 2844 ν(CH2, CH3), 2216 ν(C≡C), 1747 ν(C=O ester) 1655
Amide I., 1530 Amide II., 759 γ(=CH). MS m/z (rel int.): 231 (5, M+), 172 (38), 129 (100), 101 (8), 75 (13),
51 (5).
Methyl N-(3-phenyl-propiolyl)-valinate (11g): Yield: 194 mg (75%); pale yellow solid material, mp. 62
°C; Rf (5% EtOAc, 95% CHCl3) 0.77; δH (500 MHz, CDCl3) 7.60-7.58 (2H, m, Ar), 7.48-7.44 (1H, m, Ar),
7.41-7.38 (2H, m, Ar), 6.46 (1H, d, J= 8.7 Hz, NH), 4.70 (1H, dd, J= 8.7 Hz, 5.0 Hz, NH(CH)), 3.81 (1H, s,
CH3), 2.26 (1H, dq, J=6.9 Hz, 5.0 Hz, (CH3)2CH), 1.03 (3H, d, J= 6.9 Hz, (CH)CH3), 0.99 (3H, d, J= 6.9 Hz,
(CH)CH3). δC (125.7 MHz, CDCl3) 171.9, 153.1, 132.6, 130.2, 128.6, 120.1, 85.6, 82.7, 57.4, 52.4, 31.5, 18.9,
17.9. IR (KBr, ν (cm-1)): 3201 ν(NH), 3031 ν(CH, Ar), 2974, 2946, 2908, 2879, 2838 ν(CH2, CH3), 2221
ν(C≡C), 1736 ν(C=O ester) 1627 Amide I., 1551 Amide II., 1285 ν(C-O-C ester), 767 γ(=CH). MS m/z (rel
int.): 259 (3, M+), 244 (7), 200 (31), 129 (100), 101 (7), 75 (10), 51 (3).

13
ACCEPTED MANUSCRIPT
Methyl N-(3-phenyl-propiolyl)-prolinate (rotamer A + rotamer B) (11h): Yield: 213 mg (83%); viscous
orange material; Rf (5% EtOAc, 95% CHCl3) 0.75; δH (500 MHz, CDCl3) 7.59-7.53 (2H, m, Ar), 7.47-7.43
(1H, m, Ar), 7.41-7.37 (2H, m, Ar), 4.80-4.59 (1H, m), 3.97-3.85 (1H, m), 3.79 (3H, s rotamer A), 3.78 (3H, s
rotamer B), 3.75-3.66 (1H, m), 2.42-2.27 (1H, m), 2.21-1.97 (3H, m). δC (125.7 MHz, CDCl3) rotamer A:
172.6, 152.9, 132.6, 130.3, 128.5, 120.2, 89.3, 82.1, 61.0, 52.6, 46.1, 30.8, 23.3; rotamer B: 172.0, 153.1,
132.5, 130.1, 128.6, 120.5, 89.6, 82.3, 58.2, 52.4, 48.5, 29.8, 24.2. IR (KBr, ν (cm-1)): 3056 ν(CH, Ar), 2980,
2952, 2879, 2844 ν(CH2, CH3), 2208 ν(C≡C), 1749 ν(C=O ester) 1613 Amide I., 760 γ(=CH). MS m/z (rel
int.): 257 (7, M+), 198 (43), 129 (100), 101 (7), 75 (22), 51 (8).
Methyl N-(3-phenyl-propiolyl)-phenylalaninate (11i): Yield: 181 mg (59%); pale yellow solid material,
mp. 103-104 °C; Rf (5% EtOAc, 95% CHCl3) 0.80; δH (500 MHz, CDCl3) 7.57-7.56 (2H, m, Ar), 7.47-7.44
(1H, m, Ar), 7.41-7.38 (2H, m, Ar), 7,36-7.33 (2H, m, Ar), 7.31-7.28 (1H, m, Ar), 7.18-7.17 (2H, m, Ar), 6.45
(1H, d, J= 7.7 Hz, NH), 5.02 (1H, dt, J= 7.7 Hz, 5.6 Hz, CH), 3.79 (3H, s, CH3), 3.28-3.18 (2H, m, CH2). δC
(125.7 MHz, CDCl3) 171.3, 152.7, 135.5, 132.7, 130.2, 129.3, 128.7, 128.5, 127.3, 120.0, 85.6, 82.6, 53.6,
52.5, 37.8. IR (KBr, ν (cm-1)): 3296 ν(NH), 3082, 3063, 3031 ν(CH, Ar), 2946, 2838 ν(CH2, CH3), 2217
ν(C≡C), 1741 ν(C=O ester) 1634 Amide I., 1531 Amide II., 1486, 1436 ν(C=C), 1319 ν(C-O-C ester), 759
γ(=CH). MS m/z (rel int.): 307 (3, M+), 248 (10), 162 (28), 129 (100), 101 (7), 91 (13), 77 (11), 51 (7).
N-Methoxy-N-methyl-3-phenylpropiolamide (11j): Yield: 119 mg (63%); light brown solid material, mp.
36 °C; Rf (5% EtOAc, 95% CHCl3) 0.47; δH (500 MHz, CDCl3) 7.59 (2H, d, J=7.3 Hz, Ar), 7.47-7.44 (1H, m,
Ar), 7.41-7.31 (2H, m, Ar), 3.87 (3H, brs, OCH3), 3.32 (3H, brs, NCH3). δC (125.7 MHz, CDCl3) 154.7, 132.6,
130.2, 128.5, 120.5, 90.4, 80.8, 62.2, 32.6. IR (KBr, ν (cm-1)): 3056, 3019 ν(CH, Ar), 2971 ν(CH3), 2218
ν(C≡C), 1638 Amide I., 1492, 1472, 1461, 1447, 1415 ν(C=C), 1202 ν(C-O-C), 760 γ(=CH). MS m/z (rel int.):
189 (4, M+), 159 (4), 129 (100), 101 (8), 75 (16), 51 (6).
(S)-3-Phenyl-N-(1-phenylethyl)propiolamide (11k): Yield: 239 mg (96%); pale yellow solid material,
mp. 108 °C; Rf (5% EtOAc, 95% CHCl3) 0.82; δH (500 MHz, CDCl3) 7.56-7.29 (10 H, m, Ar), 6.24 (1H, brs,
NH), 5.29-5.23 (1H, m, CH), 1.60 (3H, d, CH3). δC (125.7 MHz, CDCl3) 152.5, 142.3, 132.5, 130.3, 128.8,
128.5, 127.7, 126.3, 120.2, 84.7, 83.1, 49.4, 21.5. IR (KBr, ν (cm-1)): 3316 ν(NH) 3085, 3063, 3031 ν(CH, Ar),
2968, 2927, 2867 ν(CH3, CH), 2215 ν(C≡C), 1623 Amide I., 1529 Amide II., 1495, 1451, 1445 ν(C=C), 762
γ(=CH). MS m/z (rel int.): 248 (21, M-1+), 206 (23), 191 (15), 129 (100), 104 (15), 77 (17), 51 (12).
17β-Hydroxy-N-(terc-butyl)-17α-pregna-4-en-20-yn-3-one-20-carboxamide (13a): Yield: 195 mg (95%);
light brown solid material, mp. 129-130 °C; Rf (50% EtOAc, 50% CHCl3) 0.58; δH (500 MHz, CDCl3) 5.75
(1H, s, 3-CH), 5.69 (1H, s, NH), 2.48-1.01 (19H, m skeleton protons), 1.38 (9H, s, C(CH3)3), 1.21 (3H, s, 19-
CH3), 0.92 (3H, s, 18-CH3). δC (125.7 MHz, CDCl3) 199.4, 170.9, 152.2, 124.0, 86.4, 81.5, 79.7, 53.0, 52.4,
50.1, 47.2, 38.7, 38.6, 36.3, 35.6, 33.9, 32.8, 32.7, 31.3, 28.6, 23.2, 20.7, 17.4, 12.7. IR (KBr, ν (cm-1)): 3325

14
ACCEPTED MANUSCRIPT
ν(OH), 2965, 2945, 2873 ν(CH2, CH3), 2221 ν(C≡C), 1659 Amide I + ν(C=O) + ν(C=C), 1531 Amide II., 1069
ν(C-OH). MS (ESI) m/z (rel int.): 412.3 (100, M+1+), MS2 m/z (rel int.): 394.3 (21), 356.2 (100), 338.2 (29),
1-(17β-Hydroxy-17α-pregna-4-en-20-yn-3-one)carbonyl-piperidine (13b):Yield: 203 mg (96%); off
white solid material, mp. 116 °C; Rf (50% EtOAc, 50% CHCl3) 0.50; δH (500 MHz, CDCl3) 5.76 (1H, s, 3-
CH), 3.72-3.64 (2H, m), 3.63-3.53 (2H, m), 2.48-1.01 (19H, m, skeleton protons), 1.72-1.57 (8H, m), 1.22
(3H, s, 19-CH3), 0.94 (3H, s 18-CH3). δC (125.7 MHz, CDCl3) 199.3, 170.7, 152.5, 124.0, 94.3, 79.8, 78.9,
53.5, 50,4, 48.2, 47.4, 42.4, 38.7, 38.6, 36.2, 35.8, 33.9, 32.8, 32.7, 31.5, 26.4, 25.3, 24.5, 23.2, 20.7, 17.5,
12.7. IR (KBr, ν (cm-1)): 3304, 3259 ν(OH), 3008, 2972, 2939, 2857 ν(CH2, CH3), 2219 ν(C≡C), 1665 ν(C=C)
+ ν(C=O), 1603 Amide I., 1070 ν(C-OH). MS (ESI) m/z (rel int.): 424.3 (100, M+1+), MS2 m/z (rel int.): 406.3
(100), MS3 m/z (rel int.): 388.3 (100), 321.2 (30), 251.1 (51), 209 (32), 138 (78).
4-(17β-Hydroxy-17α-pregna-4-en-20-yn-3-one)carbonyl-morpholine (13c) : Yield: 204 mg (96%); off
white solid material, mp. 189-190 °C; Rf (50% EtOAc, 50% CHCl3) 0.29; δH (500 MHz, CDCl3) 5.75 (1H, s,
3-CH), 3.75-3.65 (8H, m), 2.48-0.98 (19H, m, skeleton protons), 1.21 (3H, s, 19-CH3), 0.94 (3H, s 18-CH3). δC
(125.7 MHz, CDCl3) 199.3, 170.6, 152.8, 124.0, 96.0, 79.9, 78.2, 66.8, 66.4, 53.4, 50,4, 47.4, 47.2, 42.0, 38.8,
38.6, 36.3, 35.7, 33.9, 32.9, 32.7, 31.5, 23.2, 20.7, 17.4, 12.7. IR (KBr, ν (cm-1)): 3375 ν(OH), 2940, 2857
ν(CH2, CH3), 2218 ν(C≡C), 1665 ν(C=C) + ν(C=O), 1603 Amide I., 1069 ν(C-OH). MS (ESI) m/z (rel
int.):426.3 (100, M+1+), MS2 m/z (rel int.): 408.3 (100), MS3 m/z (rel int.): 390.3 (100), 321.2 (71), 303.2
(71), 275.1 (74), 251.1 (79).
17β-Hydroxy-N-(allyl)-17α-pregna-4-en-20-yn-3-one-20-carboxamide (13d):Yield: 128 mg (65%); off
white solid material, mp. 201-202 °C; Rf (50% EtOAc, 50% CHCl3) 0.43; δH (500 MHz, CDCl3) 6.10 (1H,
brs, NH), 5.90-5.80 (2H, ddd, J= 16.2 Hz, 10.4 Hz, 5.7 Hz CH=CH2), 5.75 (1H, s, 3-CH), 5.25 (1H, d, J= 16.2
Hz CH=CH2(E)), 5.19 (1H, d, J= 10.4 Hz CH=CH2(Z)), 3.93 (2H, t, J= 5.7 Hz, NCH2), 2.48-0.99 (19H, m,
skeleton protons), 1.21 (3H, s, 19-CH3), 0.92 (3H, s 18-CH3). δC (125.7 MHz, CDCl3) 199.4, 170.9, 152.9,
133.2, 124.0, 117.3, 88.9, 80.4, 79.7, 53.1, 50.2, 47.3, 42.3, 38.7, 38.6, 36.3, 35.7, 33.9, 32.8, 32.7, 31.4, 23.2,
20.7, 17.5, 12.7. IR (KBr, ν (cm-1)): 3299 ν(OH), 2983, 2973, 2943, 2908, 2883, 2853 ν(CH2, CH3), 2220
ν(C≡C), 1652 Amide I + ν(C=O) + ν(C=C), 1520 Amide II., 1068 ν(C-OH). MS (ESI) m/z (rel int.):396.3
(100, M+1+), MS2 m/z (rel int.): 378.3 (100), MS3 m/z (rel int.): 360.3 (45), 337.2 (100), 321.3 (26).
(17β-Hydroxy-17α-pregna-4-en-20-yn-3-one)carbonyl-glycine methyl ester (13e) : Yield: 196 mg (92%);
pale yellow solid material, mp. 191 °C; Rf (50% EtOAc, 50% CHCl3) 0.31; δH (500 MHz, CDCl3) 6.75 (1H,
brs, NH), 5.75 (1H, s, 3-CH), 4.11 (2H, d, J= 5.1 Hz), 3.80 (3H, s, CH3), 2.48-0.99 (19H, m, skeleton protons),
1.21 (3H, s, 19-CH3), 0.92 (3H, s 18-CH3). δC (125.7 MHz, CDCl3) 199.4, 170.9, 169.9, 153.1, 124.0, 90.1,
79.9, 79.6, 53.1, 52.6, 50.2, 47.3, 41.3, 38.6, 36.3, 35.6, 33.9, 32.8, 32.7, 31.4, 23.2, 20.7, 17.4, 12.7. IR (KBr,
ν (cm-1)): 3331 ν(OH), 2975, 2949, 2887, 2862 ν(CH2, CH3), 2225 ν(C≡C), 1730 ν(C=O ester), 1667 ν(C=C) +

15
ACCEPTED MANUSCRIPT
ν(C=O) + Amide I., 1539 Amide II., 1062 ν(C-OH). MS (ESI) m/z (rel int.):428.3 (100, M+1+), MS2 m/z (rel
int.): 410.3 (100), 378.2 (28), 350.3 (13), 321.2 (13).
(17β-Hydroxy-17α-pregna-4-en-20-yn-3-one)carbonyl-L-alanine methyl ester (13f): Yield: 199 mg
(90%); light brown solid material, mp. 152-153 °C; Rf (50% EtOAc, 50% CHCl3) 0.40; δH (500 MHz, CDCl3)
6.88 (1H, d, J= 7.2 Hz, NH), 5.75 (1H, s, 3-CH), 4.68-4.62 (1H, m), 3.78 (3H, s, CH3), 2.48-1.00 (19H, m,
skeleton protons), 1.45 (3H, d, J= 7.2 Hz, CH3), 1.21 (3H, s, 19-CH3), 0.92 (3H, s 18-CH3). δC (125.7 MHz,
CDCl3) 199.4, 173.2, 170.9, 152.6, 124.0, 89.7, 80.1, 79.6, 53.1, 52.7, 50.2, 48.3, 47.3, 38.7, 38.6, 36.3, 35.6,
33.9, 32.8, 32,7, 31.3, 23.2, 20.7, 18,2, 17.4, 12.7. IR (KBr, ν (cm-1)): 3360, 3309 ν(OH), 2976, 2946, 2878,
2860 ν(CH2, CH3, CH), 2220 ν(C≡C), 1743 ν(C=O ester), 1668, 1625 ν(C=C) + ν(C=O) + Amide I., 1529
Amide II., 1069 ν(C-OH). MS (ESI) m/z (rel int.):442.4 (100, M+1+), MS2 m/z (rel int.): 424.3 (100), 410.2
(11), 392.2 (56), 364.2 (57), 321.2 (12).
(17β-Hydroxy-17α-pregna-4-en-20-yn-3-one)carbonyl-L-valine methyl ester (13g) : Yield: 141 mg
(60%); pale yellow solid material, mp. 169-170 °C; Rf (50% EtOAc, 50% CHCl3) 0.53; δH (500 MHz, CDCl3)
6.90 (1H, d, J= 9.0 Hz, NH), 5.76 (1H, s, 3-CH), 4.62 (1H, dd, J= 9.0 Hz, 5.2 Hz), 3.78 (3H, s, CH3), 2.48-
1.01 (19H, m, skeleton protons), 2.21 (1H, dq, J= 6.8 Hz, 5.2 Hz), 1.21 (3H, s, 19-CH3), 0.99 (3H, d, J= 6.8
Hz), 0.97 (3H, d, J= 6.8 Hz), 0.93 (3H, s 18-CH3). δC (125.7 MHz, CDCl3) 199.5, 172.3, 171.0, 153.3, 124.0,
90.1, 80.1, 79.6, 57.4, 53.0, 52.4, 50.1, 47.2, 38.7, 38.6, 36.3, 35.6, 33.9, 32.8, 32.7, 31.4, 31.3, 23.3, 20.7,
18.9, 17.9, 17.4, 12.7. IR (KBr, ν (cm-1)): 3433, 3350 ν(OH), 2951, 2876 ν(CH2, CH3), 2223 ν(C≡C), 1736
ν(C=O ester), 1676 ν(C=C) + ν(C=O), 1639 Amide I., 1535 Amide II., 1069 ν(C-OH). MS (ESI) m/z (rel
int.):470.4 (100, M+1+), MS2 m/z (rel int.): 452.3 (100), 438.3 (21), 420.3 (58), 410.3 (36), 392.3 (72), 321
(7).
(17β-Hydroxy-17α-pregna-4-en-20-yn-3-one)carbonyl-L-proline methyl ester ( rotamer A+ rotamer B)
(13h):Yield: 152 mg (65%); off white solid material, mp. 130-131 °C; Rf (50% EtOAc, 50% CHCl3) 0.32; δH
(500 MHz, CDCl3) 5.76 (1H, s, 3-CH), 4.62-4.50 (1H, m, rotamer A+ rotamer B), 3.84-3.59 (6H, m), 3.77
(3H, s, rotamer A), 3.76 (3H, s, rotamer B), 2.49-0.97 (19H, m, skeleton protons), 1.22 (3H, s, 19-CH3,
rotamer A), 1.21 (3H, s, 19-CH3, rotamer B), 0.94 (3H, s 18-CH3, rotamer A), 0.92 (3H, s 18-CH3, rotamer B).
δC (125.7 MHz, CDCl3) rotamer A+ rotamer B 199.4, 172.8, 172.0, 171.9, 170.9, 170.8, 152.6, 152.5, 124.0,
94.0, 93.7, 79.8, 79.7, 61.2, 58.2, 53.3, 53.1, 52.7, 52.4, 50.3, 50.2, 48.4, 47.3, 47.2, 46.1, 38.8, 38.6, 38.5,
36.2, 35.7, 34.0, 32.8, 32.7, 31.4, 31.3, 30.7, 29.7, 24.2, 23.3, 23.2, 23.1, 20.7, 17.4, 12.7, 12.6. IR (KBr, ν
(cm-1)): 3257 ν(OH), 2974, 2945, 2914, 2891, 2859 ν(CH2, CH3), 2221 ν(C≡C), 1743 ν(C=O ester), 1714
ν(C=O), 1671 ν(C=C), 1608 Amide I., 1078 ν(C-OH). MS (ESI) m/z (rel int.):468.3 (100, M+1+), MS2 m/z
(rel int.): 450.3 (100), 390.2 (15), MS3 (450.3) m/z (rel int.): 390 (100), 321.2 (26), 303.2 (8)
(17β-Hydroxy-17α-pregna-4-en-20-yn-3-one)carbonyl-L-phenylalnine methyl ester (13i) : Yield: 145 mg
(56%); pale yellow solid material, mp. 85-86 °C; Rf (50% EtOAc, 50% CHCl3) 0.53; δH (500 MHz, CDCl3)

16
ACCEPTED MANUSCRIPT
7.32-7.25 (3H, m, Ar), 7.16-7.13 (2H, m, Ar), 6.81 (1H, d, J= 7.8 Hz), 5.76 (1H, s, 3-CH), 4.93-4.89 (1H, m),
3.74 (3H, s, CH3), 3.17-3.08 (2H, m, Ph(CH2)), 2.48-0.98 (19H, m, skeleton protons), 1.21 (3H, s, 19-CH3),
0.91 (3H, s 18-CH3). δC (125.7 MHz, CDCl3) 199.5, 171.7, 171.1, 152.8, 135.5, 129.3, 128.6, 127.3, 123.9,
90.1, 79.9, 79.5, 53.6, 53.1, 52.5, 50.1, 47.3, 38.7, 38.6, 37.7, 36.2, 35.6, 33.9, 32.8, 32,7, 31.3, 23.2, 20.7,
17.4, 12.7. IR (KBr, ν (cm-1)): 3413 ν(OH), 3029, 3015 ν(CH, Ar), 2947, 2875, 2857 ν(CH2, CH3, CH), 2223
ν(C≡C), 1745 ν(C=O ester), 1659 ν(C=C) + ν(C=O) + Amide I., 1529 Amide II., 1069 ν(C-OH). MS (ESI) m/z
(rel int.):518.3 (100, M+1+), MS2 m/z (rel int.): 500.3 (100), 486.3 (11), 468.3 (29), 458.2 (11), 440.3 (66). 321
(6).
17β-Hydroxy-(N-methyl-N-methoxy)-17α-pregna-4-en-20-yn-3-one-20-carboxamide (13j) : Yield: 150
mg (75%); light brown solid material, mp. 182 °C; Rf (50% EtOAc, 50% CHCl3) 0.37; δH (500 MHz, CDCl3)
5.76 (1H, s, 3-CH), 3.78 (3H, s, OCH3), 3.25 (3H, brs, NCH3), 2.47-0.97 (19H, m, skeleton protons), 1.22 (3H,
s, 19-CH3), 0.95 (3H, s 18-CH3). δC (125.7 MHz, CDCl3) 199.4, 170.8, 154.2, 124.0, 94.4, 79.8, 78.2, 62.2,
53.5, 50,3, 47.4, 38.7, 38.6, 36.2, 35.8, 33.9, 32.8, 32.7, 32.4, 31.5, 23.2, 20.7, 17.4, 12.7. IR (KBr, ν (cm-1)):
3351 ν(OH), 2974, 2946, 2882, 2857 ν(CH2, CH3), 2225 ν(C≡C), 1671 ν(C=O), 1639 ν(C=C), 1613 Amide I.,
1069 ν(C-OH). MS (ESI) m/z (rel int.):400.3 (100, M+1+), MS2 m/z (rel int.): 382.3 (100), 321,2 (30), 293.2
(14).
17β-Hydroxy-N-((S)-1-phenylethyl)-17α-pregna-4-en-20-yn-3-one-20-carboxamide (13k): Yield: 179
mg (78%); light brown solid material, mp. 119 °C; Rf (50% EtOAc, 50% CHCl3) 0.48; δH (500 MHz, CDCl3)
7.39-7.29 (5H, m, Ar), 6.23 (1H, d, J= 7.5 Hz, NH), 5.75 (1H, s, 3-CH), 5.17 (1H, dq, J= 7.5 Hz, 7.0 Hz,
(CH3)CH), 2.64-1.0 (19H, m, skeleton protons), 1.54 (3H, d, J= 7.0 Hz), 1.21 (3H, s, 19-CH3), 0.92 (3H, s 18-
CH3). δC (125.7 MHz, CDCl3) 199.5, 171.0, 152.1, 142.1, 128.8, 127.7, 126.4, 124.0, 88.70, 80.6, 79.8, 53.0,
50,1, 49.4, 47.3, 38.7, 38.6, 36.3, 35.6, 33.9, 32.8, 32.7, 31.3, 23.2, 21.3, 20.7, 17.4, 12.7. IR (KBr, ν (cm-1)):
3394, 3303 ν(OH), 3060, 3029 ν(CH Ar), 2974, 2945, 2873 ν(CH2, CH3), 2222 ν(C≡C), 1656 Amide I +
ν(C=O) + ν(C=C), 1530 Amide II., 1069 ν(C-OH). MS (ESI) m/z (rel int.):460.3 (100, M+1+), MS2 m/z (rel
int.): 356.2 (100), 338.3 (8), MS3 (338.3) m/z (rel int.): 321.2 (100), 310.2 (75), 293.2 (29), 202.1 (33).
N-(tert-Butyl)-3-(cyclohex-1-en-1-yl)propiolamide (14a): Yield: 108 mg (53%); yellow solid material,
mp. 78 °C; Rf (5% EtOAc, 95% CHCl3) 0.91; δH (500 MHz, CDCl3) 6.33 (1H, s, =CH), 5.64 (1H, brs, NH),
2.15-2.12 (4H, m), 1.68-1.58 (4H, m), 1.39 (9H, s, C(CH3)3) δC (125.7 MHz, CDCl3) 153.0, 139.6, 118.8,
84.6, 82.0, 52.2, 28.6, 28.2, 25.8, 22.0, 21.2. IR (KBr, ν (cm-1)): 3241 ν(NH), 3052 ν(=CH), 2967, 2924, 2859
ν(CH2, CH3) 2208 ν(C≡C), 1620 ν(C=C) + Amide I., 1537 Amide II., 1454. MS m/z (rel int.): 205 (18, M+),
190 (24), 175 (2), 161 (2), 150 (18), 133 (100), 105 (15), 77 (22), 51 (7).
3-(Cyclohex-1-en-1-yl)-1-(piperidin-1-yl)prop-2-yn-1-one (14b): Yield: 128 mg (59%); red oil; Rf (5%
EtOAc, 95% CHCl3) 0.84; δH (500 MHz, CDCl3) 6.37-6.34 (1H, m, =CH), 3.69 (2H, t, J= 5.6 Hz), 3.59 (2H, t,
J= 5.6 Hz), 2.20-2.13 (4H, m), 1.68-1.65 (2H, m), 1.64-1.60 (2H, m), 1.58-1.54 (2H, m). δC (125.7 MHz,

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CDCl3) 153.4, 139.4, 119.2, 92.4, 79.3, 48.1, 42.3, 28.4, 26.4, 25.9, 25.4, 24.6, 22.0, 21.2. IR (KBr, ν (cm-1)):
2935, 2857 ν(CH2) 2197 ν(C≡C), 1628 ν(C=C)+ Amide I., 1433. MS m/z (rel int.): 217 (100, M+), 202 (42),
188 (52), 160 (29), 136 (48), 133 (93), 105 (42), 84 (57), 80 (63), 77 (78), 55 (26).
3-(Cyclohex-1-en-1-yl)-1-morpholinoprop-2-yn-1-one (14c): Yield: 120 mg (55%); yellow solid
material, mp. 49 °C; Rf (5% EtOAc, 95% CHCl3) 0.67; δH (500 MHz, CDCl3) 6.37 (1H, m, =CH), 3.76-3.74
(2H, m), 3.71-3.70 (2H, m), 3.66 (4H, brs), 2.16-2.14 (4H, m), 1.68-1.58 (4H, m). δC (125.7 MHz, CDCl3)
153.6, 140.2, 118.9, 93.3, 78.6, 66.9, 66.5, 47.2, 41.9, 28.3, 25.9, 21.9, 21.1. IR (KBr, ν (cm-1)): 2926, 2904,
2864 ν(CH2), 2197 ν(C≡C), 1613 ν(C=C) + Amide I., 1427, 1271, 1253, 1113 ν(C-O-C). MS m/z (rel int.):
219 (48, M+), 204 (5), 190 (12), 133 (100), 105 (26), 86 (48), 77 (45), 56 (33).
Methyl (3-(cyclohex-1-en-1-yl)propioloyl)glycinate (14e): Yield: 130 mg (59%); yellow oil; Rf (5%
EtOAc, 95% CHCl3); 0.67; δH (500 MHz, CDCl3) 6.43 (1H, brs, NH), 6.39 (1H, brs, =CH), 4.11 (2H, d, J= 5.3
Hz), 3.79 (3H, s, CH3), 2.17-2.14 (4H, m), 1.68-1.58 (4H, m). δC (125.7 MHz, CDCl3) 169.8, 153.8, 140.8,
118.6, 87.9, 80.3, 52.5, 41.4, 28.2, 25.9, 21.9, 21.1. IR (KBr, ν (cm-1)): 3276 ν(NH), 2935, 2860 ν(CH2, CH3),
2206 ν(C≡C), 1745 ν(C=O ester), 1636 ν(C=C) + Amide I., 1533 Amide II., 1300, 1210 ν(C-O-C ester), 1180.
MS m/z (rel int.): 221 (20, M+), 206 (1), 190 (2), 162 (11), 133 (100), 105 (13), 77 (22), 51 (8).
Methyl (3-(cyclohex-1-en-1-yl)propioloyl)-L-alaninate (14f): Yield: 110 mg (47%); yellow oil; Rf (5%
EtOAc, 95% CHCl3) 0.81; δH (500 MHz, CDCl3) 6.44 (1H, d, J= 7.2 Hz, NH), 6.39 (1H, s, =CH), 4.69-4.63
(1H, m, CH), 3.79 (3H, s, CH3), 2.17-2.14 (4H, m), 1.69-1.59 (4H, m), 1.46 (3H, d, J= 7.2 Hz, CH3). (125.7
MHz, CDCl3) 172.9, 153.1, 140.6, 118.6, 87.5, 80.5, 52.6, 48.3, 28.2, 25.9, 22.0, 21.1, 18.4. IR (KBr, ν (cm-
1)): 3272 ν(NH), 3029 ν(=CH), 2987, 2934, 2860 ν(CH2, CH3), 2203 ν(C≡C), 1740 ν(C=O ester), 1645 ν(C=C)
+ Amide I., 1528 Amide II., 1213 ν(C-O-C ester), 1179. MS m/z (rel int.): 235 (7, M+), 204 (1), 176 (43), 133
(100), 105 (9), 77 (17), 51 (6).
3-(Cyclohex-1-en-1-yl)-N-methoxy-N-methylpropiolamide (14j): Yield: 68 mg (35%); red oil; Rf (5%
EtOAc, 95% CHCl3) 0.81; δH (500 MHz, CDCl3) 6.42 (1H, brs, =CH), 3.80 (3H, s, -OCH3), 3.26 (3H, brs, -
NCH3), 2.20-20.16 (4H, m), 1.68-1.62 (4H, m). δC (125.7 MHz, CDCl3) 155.1, 140.7, 119.0, 92.8, 78.7, 61.9,
32.5, 28.3, 25.9, 22.0, 21.2. IR (KBr, ν (cm-1)): 2934, 2860 ν(CH2, CH3), 2205 ν(C≡C), 1642 ν(C=C) + Amide
I., 1412, 1381 ν(C-O-C), 720 γ(=CH). MS m/z (rel int.): 193 (<1, M+), 163 (75), 133 (100), 105 (46), 77 (57),
51 (24).
N-(tert-Butyl)hept-2-ynamide (15a): Yield: 102 mg (56%); yellow solid material, mp. 32 °C; Rf (5%
EtOAc, 95% CHCl3) 0.85; δH (500 MHz, CDCl3) 5.60 (1H, brs, NH), 2.28 (2H, t, J= 7.1 Hz), 1.57-1.50 (2H,
m), 1.47-1.41 (2H, m), 1.38 (9H, s, C(CH3)3), 0.93 (3H, t, J= 7.3 Hz). δC (125.7 MHz, CDCl3) 152.8, 85.1,
76.6, 52.1, 29.8, 28.6, 22.0, 18.2, 13.5. IR (KBr, ν (cm-1)): 3324 ν(NH), 2967, 2932, 2873 ν(CH2, CH3), 2239
ν(C≡C), 1638 Amide I., 1522 Amide II., 1451, 1288, 1221. MS m/z (rel int.): 181 (23, M+), 166 (90), 152 (1),
138 (6), 126 (100), 109 (92), 79 (39), 58 (96).

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1-(Piperidin-1-yl)hept-2-yn-1-one (15b): Yield: 124 mg (64%); red oil; Rf (5% EtOAc, 95% CHCl3)
0.78; δH (500 MHz, CDCl3) 3.70-3.67 (2H, m), 3.58-3.55 (2H, m), 2.36 (2H, t, J= 7.1 Hz), 1.67-1.64 (2H, m),
1.62-1.54 (6H, m), 1.48-1.40 (2H, m), 0.93 (3H, t, J= 7.3 Hz). δC (125.7 MHz, CDCl3) 153.2, 93.1, 73.9, 48.1,
42.2, 29.9, 26.4, 25.4, 24.5, 22.0, 18.7, 13.5. IR (KBr, ν (cm-1)): 2939, 2858 ν(CH2, CH3), 2237 ν(C≡C), 1616
Amide I., 1435 Amide II., 1268, 732. MS m/z (rel int.): 193 (16, M+), 178 (2), 164 (11), 150 (100), 136 (10),
109 (16), 84 (22), 79 (20), 67 (7), 53 (15).
1-Morpholinohept-2-yn-1-one (15c): Yield: 185 mg (95%); red oil; Rf (5% EtOAc, 95% CHCl3) 0.64; δH
(500 MHz, CDCl3) 3.77-3.75 (2H, m), 3.72-3.70 (2H, m), 3.67-3.64 (4H, m), 2.37 (2H, t, J= 7.1 Hz), 1.62-
1.55 (2H, m), 1.47-1.40 (2H, m), 0.93 (3H, t, J= 7.3 Hz). δC (125.7 MHz, CDCl3) 153.4, 94.2, 73.3, 66.9, 66.5,
47.2, 41.8, 29.8, 22.0, 18.6, 13.5. IR (KBr, ν (cm-1)): 2960, 2931, 2860 ν(CH2, CH3), 2238 ν(C≡C), 1623
Amide I., 1429, 1276, 1247, 1150 ν(C-O-C), 1010, 732. MS m/z (rel int.): 195 (35, M+), 180 (20), 166 (20),
152 (36), 109 (47), 86 (100), 56 (82)
Methyl hept-2-ynoylglycinate (15e): Yield: 105 mg (53%); yellow oil; Rf (5% EtOAc, 95% CHCl3) 0.65;
δH (500 MHz, CDCl3) 6.38 (1H, brs, NH), 4.09 (2H, d, J= 5.1 Hz), 3.79 (3H, s, CH3), 2.33 (2H, t, J= 7.1 Hz),
1.59-1.53 (2H, m), 1.48-1.40 (2H, m), 0.93 (3H, t, J= 7.3 Hz). δC (125.7 MHz, CDCl3) 169.8, 153.5, 88.7,
74.9, 52.5, 41.3, 29.7, 21.9, 18.3, 13.5. IR (KBr, ν (cm-1)): 3301 ν(NH), 3054, 2958, 2874 ν(CH2, CH3), 2233
ν(C≡C), 1757 ν(C=O ester), 1653 Amide I., 1529 Amide II., 1287, 1212 ν(C-O-C ester), 1008, 744. MS m/z
(rel int.): 197 (1, M+), 182 (1), 168 (2), 155 (7), 138 (44), 109 (100), 79 (24), 66 (13), 52 (15).
Methyl hept-2-ynoyl-L-alaninate (15f): Yield: 182 mg (86%); yellow oil; Rf (5% EtOAc, 95% CHCl3)
0.75; δH (500 MHz, CDCl3) 6.41 (1H, brs, NH), 4.67-4.59 (1H, m), 3.78 (3H, s, OCH3), 2.33-2.30 (2H, m),
1.59-1.53 (2H, m), 1.45-1.42 (5H, m), 0.95-0.91 (3H, m, CH3). δC (125.7 MHz, CDCl3) 172.9, 152.9, 88.2,
75.1, 52.6, 48.2, 29.7, 21.9, 18.3, 18.2, 13.5. IR (KBr, ν (cm-1)): 3289 ν(NH), 3041, 2958, 2874 ν(CH2, CH3),
2237 ν(C≡C), 1749 ν(C=O ester), 1636 Amide I., 1533 Amide II., 1456, 1271, 1213, 1162 ν(C-O-C ester),
744. MS m/z (rel int.): 211 (1, M+), 196 (1), 173 (23), 152 (90), 109 (100), 79 (32), 53 (18).
N-Methoxy-N-methylhept-2-ynamide (15j): Yield: 88 mg (52%); red oil; Rf (5% EtOAc, 95% CHCl3)
0.75; δC (125.7 MHz, CDCl3) 154.8, 93.7, 73.2, 62.0, 32.3, 29.8, 21.9, 18.7, 13.5. δH (500 MHz, CDCl3) 3.78
(3H, s, -OCH3), 3.24 (3H, brs, -NCH3), 2.42-2.39 (2H, m), 1.62-1.56 (2H, m), 1.49-1.44 (2H, m), 0.96-0.92
(3H, m, CH3). IR (KBr, ν (cm-1)): 2961, 2936, 2874 ν(CH2, CH3), 2237 ν(C≡C), 1644 Amide I., 1460, 1380
ν(C-O-C), 724. MS m/z (rel int.): 169 (2, M+), 154 (<1), 141 (1), 127 (6), 109 (100), 79 (44), 66 (14), 53 (30).
Ethyl (E)-3-(tert-butylamino)acrylate (16): MS m/z (rel int.): 171 (M+, 65), 156 (11), 141 (97), 126
(100), 98 (65), 56 (48).

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Acknowledgement: The authors thank the Hungarian Research Fund (K113177) for the financial support.
This work was supported by the GINOP-2.3.2-15-2016-00049 grant. P. Sz. thanks Talentum Fund of the
Gedeon Richter Chemical Works Ltd. for the scholarship. The present scientific contribution is dedicated to
the 650th anniversary of the foundation of the University of Pécs, Hungary
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Captions
Scheme 1. Synthesis of iodoalkynes (2, 4, 6, 8 and 10) and bromoalkyne (2’) used as substrates in
further aminocarbonylations
Scheme 2. Reactions of 10 under aminocarbonylation conditions (formation of enamines accompanied
by deiodination)