Facile direct synthesis of acetylenedicarboxamides

Article abstract of DOI:10.1055/s-0033-1341101

A convenient, rapid and widely applicable one-pot procedure has been developed for the synthesis of acetylenedicarboxamides from various primary and secondary amines, including amino acid derivatives, protected carbohydrates, and fluorescent labels. By using DMTMM for amide coupling, acetylenedicarboxylic acid was directly converted into acetylenedicarboxamides in highly competitive overall yields (52-80%). Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341101

PAPER
▌1463
paper
Facile Direct Synthesis of Acetylenedicarboxamides
Synthesis of Acetylenedicarboxamides
Dirk Heyl, Wolf-Dieter Fessner*
Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss-Straße 4, 64287 Darmstadt, Germany
Fax +49(6151)166636; E-mail: fessner@tu-darmstadt.de
Received: 13.01.2014; Accepted after revision: 11.02.2014
formation of an ionic ammoniumcarboxylate intermediate
Abstract: A convenient, rapid and widely applicable one-pot pro-
in the reaction mechanism.
cedure has been developed for the synthesis of acetylenedicarbox-
amides from various primary and secondary amines, including
amino acid derivatives, protected carbohydrates, and fluorescent la-
O
bels. By using DMTMM for amide coupling, acetylenedicarboxylic
acid was directly converted into acetylenedicarboxamides in highly
competitive overall yields (52–80%).
Br
Cl
O
R1
N
Br
i), ii)
iii), iv)
Key words: alkynes, amides, carboxylic acids, coupling, conden-
sation
Cl
O
O
OH
OH
O
O
2
R2
R2
direct
coupling
Acetylenedicarboxylic acid (ADA, 1) and its derivatives
are widely used compounds in the synthesis of carbo- and
heterocycles. In the case of acetylenedicarboxylic acid di-
esters the electron-deficient triple bond readily reacts as a
dipolarophile or dienophile in thermal cycloadditions, and
as a conjugate acceptor in Michael additions.1 Often, both
types of reaction pathways are involved in the synthesis of
heterocyclic systems when using ADA derivatives.2 As
part of our ongoing research on the multidecoration of na-
noscaffolds by ‘click’-type conjugation reactions,3 in par-
ticular by using ADA diesters as both functionalizing and
branching elements,3a we were interested in acetylenedi-
carboxylic diamides (ADCAs) as chemically more stable
analogues of diesters. However, the formation of amides
of ADA 1 suffers from competing and/or subsequent
Michael additions of the amine component because of the
highly electrophilic nature of the conjugated triple bond.
Only a few general protocols for the preparation of
ADCAs have been described (Scheme 1) that are based on
acid halides such as dibromofumaroyl dichloride (2)4 or
acetylenedicarbonyl difluoride (3).5 Reports on the use of
acetylenedicarbonyl dichloride (4) remain controversial,6
with only few applications for the synthesis of ADCAs;7
mixed anhydrides of 1 tend to polymerize.8 All these pro-
tocols require several steps and involve sensitive reagents
or intermediates. The widely applied standard technique
for direct amide coupling using carbodiimides seems to be
generally inefficient in the case of 1,9 and our attempts to
prepare ADCAs via carbonyldiimidazole activation10 also
resulted in no product formation.
N
R1
O
X
v)
iii)
1
3 X = F
4 X = Cl
O
X
Scheme 1 Common strategies for the synthesis of acetylenedicar-
boxamides: Reagents and conditions: (i) Br2; (ii) PCl5; (iii) R1NHR2;
(iv) Zn; (v) SF4 (X = F) or SOCl2 (X = Cl).
From the broad range of peptide-coupling reagents12 4-
(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholini-
um chloride (DMTMM, 5),13 which is commercially
available or can be readily prepared from cyanuric chlo-
ride in two steps,14,15 seemed to be a reagent that could ful-
fill this condition. Indeed, when using a slightly modified
Kunishima protocol15 for a test reaction of 1 with 2-
phenylethylamine (6a) in tetrahydrofuran the desired
N1,N4-diphenethylbut-2-ynediamide (7a) was isolated in
59% yield.
However, the addition of amines to 1 dissolved in tetrahy-
drofuran or ethyl acetate16 often resulted in the formation
of gummy gels, and the yields proved to be erratic. In the
search for a better solvent, the latter needed to dissolve
polar and/or ionic starting materials, intermediates, and
products, but not decompose DMTMM 5. From test reac-
tions [0.05 M 1, 6a (1.1 equiv), 5 (1.5 equiv), 20 °C, 5 h,
workup A] with methanol,17 N,N-dimethylformamide,18
or N-methylpyrrolidin-2-one19 as the solvents, the use of
methanol gave only low yields of 7a (16%) whereas N,N-
dimethylformamide or N-methylpyrrolidin-2-one gave
promising results (DMF, 48%; NMP, 52%). Aqueous
(10%, v/v) solvent mixtures gave significantly lower
yields than neat organic solvents, and no diamide product
was isolated from reactions in pure water. N-Methylpyr-
rolidin-2-one was finally chosen as the solvent for all fur-
ther investigations because isolated yields on average
were slightly higher. Concentrations of 1 in N-methylpyr-
On the assumption that ADA deprotonation should render
the triple bond more electron rich11 and hence more stable
to conjugate nucleophilic attack by amines, we, therefore,
searched for a coupling reagent that involves the incipient
SYNTHESIS 2014, 46, 1463–1468
Advanced online publication: 17.03.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1341101; Art ID: SS-2014-T0039-OP
© Georg Thieme Verlag Stuttgart · New York

1464
D. Heyl, W.-D. Fessner
PAPER
rolidin-2-one as high as 0.3 M were used to reduce the to-
tal volume, and reactions were conducted at 0 °C to avoid
decomposition of dissolved 1 and to minimize the decom-
position of reagent 5.15 Under the improved conditions
[0.3 M 1, amine (1.1 equiv), 5 (1.5 equiv), 0 °C, 5 h] pure
diamide 7a was isolated in 73% yield (Scheme 2).
Table 1 One-Pot Synthesis of Diamides 7 from Acetylenedicarbox-
ylic Acid (1) and Various Amines Using DMTMM 5
O
O
R1
R2
O
O
DMTMM
+ 2
HN
NMP, 0 °C
R1
N
N
R2
R1
HO
OH
R2
1
6
7
Entry Amine R1R2NH
Product
Yield
(%)
Me +NH
Cl–
O
Bn
NH2
6a
9
1
2
6a Ph(CH2)2NH2
6b PrNH2
7a
73
59
63
67
62
80
72
62
68
70
54
61
67
52
69
trace
58
63
64
71
65
69
65
61
59
trace
H
N
O
O
OH
O
O
Bn
Bn
7b5
7c
NMP
0 °C
1
7a
3
6c BuNH2
4
6d Me(CH2)5NH2
6e allylNH2
7d
7e5
7f
OH
N
H
5
MeO
O
N Me
6
6f propargylNH2
6g BnNH2
N
NH
N
N+
Cl–
O
7g5
7h
7i5
7j
N
7
MeO
N
OMe
MeO
5
8
8
6h piperonylamine
6i CyNH2
Scheme 2 Synthesis of diamide 7a by direct coupling of acetylenedi-
carboxylic acid (1) and 2-phenylethylamine (6a) promoted by the
DMTMM reagent 5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
6j (R)-1-phenylethylamine
6k PhNH2
7k
7l
Indeed, a variety of primary and secondary amines or their
respective ammonium salts were also directly converted
into the corresponding dicarboxamides (Table 1). Only
sterically hindered amines [e.g., dicyclohexylamine (6p)]
or amines with low nucleophilicity [e.g., 2,3,4,6-tetra-O-
acetyl-β-D-glucopyranosylamine (6z)] gave low yields of
the corresponding ADCAs under such conditions.
6l 4-MeOC6H4NH2
6m Bu2NH
7m4,5
7n
7o
6n (allyl)2NH2
6o Bn2NH
6p Cy2NH
7p
7q4,5
7r
The crude product often contained significant amounts of
the byproduct 6-dimethoxy-1,3,5-triazin-2(1H)-one (8)
despite extensive aqueous extraction, which can render
purification challenging. In most cases it was found help-
ful to first remove most of 8 by crystallization from tetra-
hydrofuran, followed by product purification from the
remaining crude mixture by chromatography and/or re-
crystallization. While screening reactions were usually
performed on a 5-mmol scale, an exemplary 40-mmol
preparative scale-up with amine 6a proceeded without a
decrease in the yield. Considering that the synthesis re-
quires two successive coupling steps, overall yields of
ADCAs 7a–y are quite satisfactory.
6q pyrrolidine
6r BnNHMe
6s H-Gly-OEt·HCl
6t H-Leu-OMe·HCl
6u H-Phe-OMe·HCl
6v H-D-Phg-OMe·HCl
6w L-(–)-ephedrine
6x dansylNH(CH2)3NH2
7s
7t
7u
7v
7w
7x
6y Ac5-β-D-Galp-O(CH2)2NH2·TosOH
6z Ac5-β-D-Glcp-NH2
7y
The ADCAs are mostly solids (except for 7m and 7n) and
crystallize as fine needles. Because of the partial double-
bond character of the amide bond that causes diastereomer
formation, nitrogen substituents can give up to four sets of
7z
signals in their H and 13C NMR spectra. Monoalkyl-
1
In conclusion, a mild and rather general one-pot proce-
dure has been developed that allows the direct conversion
of 1 with free amines or their ammonium salts into the cor-
responding ADCA in good overall yields by using DMT-
MM 5 in N-methylpyrrolidin-2-one as the coupling
reagent, with minimal loss of material from competing
Michael reactivity.
amides (e.g., 6a) show one strong signal set correspond-
ing to the predominating cis/cis conformer20 and only
minor other sets, while diamides of symmetrical dialkyl-
amines (e.g., 7m) display only two signal sets. Spectra of
ADCAs from unsymmetrical dialkylamines (e.g., 7r)
1
show four sets of H NMR signals with almost identical
relative intensities.
Synthesis 2014, 46, 1463–1468
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Acetylenedicarboxamides
1465
Starting materials and reagents were purchased from commercial
suppliers and used without purification. Analytical TLC was per-
formed on silica gel F254 (E. Merck, Darmstadt) with UV detection
followed by charring with KMnO4 or anisaldehyde stain. Column
chromatography was performed using silica gel 60 (0.06–0.2 mm;
Roth, Karlsruhe). Petroleum ether = PE. NMR spectra were record-
ed on Bruker DRX 500 or Bruker 300 MHz Avance II spectrome-
ters at r.t. FT-IR spectra were measured by Perkin-Elmer Paragon
1000 PC. ESI-MS spectra were recorded using a Bruker-Franzen
Esquire-LC mass spectrometer and EI-MS spectra with Varian
MAT 212. Combustion analysis was performed on an Elementar
Vario EL instrument. Melting points were measured on a Büchi
SMP-20 apparatus and are uncorrected.
Anal. Calcd for C10H16N2O2: C, 61.20; H, 8.22; N, 14.27. Found: C,
60.93; H, 8.17; N, 14.12.
N1,N4-Dibutylbut-2-ynediamide (7c)
Following the general procedure, workup A yielded 7c (0.71 g,
63%) as a colorless solid; mp 142 °C (CH2Cl2–PE).
IR (KBr): 3285, 3059, 2960, 2868, 1638, 1544, 1291 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.28 (t, J = 5.5 Hz, 2 H), 3.29 (dt,
J = 7.1, 5.5 Hz, 4 H), 1.61–1.47 (m, 4 H), 1.39–1.32 (m, 4 H), 0.92
(t, J = 7.4 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 151.87, 76.75, 39.80, 30.97,
19.95, 13.58.
HRMS (EI): m/z [M]+ calcd for C12H20N2O2: 224.1525; found:
224.1501.
Reaction of 1 with Amines; General Procedure
To a stirred solution of acetylenedicarboxylic acid (1, 0.57 g, 5
mmol) in NMP (10 mL) at 0 °C a solution of the amine (12 mmol,
2.4 equiv) in NMP (5 mL) [for ammonium salts additionally NMM
(2 mL) was used] was added dropwise. After 10 min DMTMM 5
(4.0 g, 14 mmol, 2.8 equiv) was added and the mixture was stirred
for 5 h.
Anal. Calcd for C12H20N2O2: C, 64.26; H, 8.99; N, 12.49. Found: C,
64.27; H, 8.99; N, 12.36.
N1,N4-Dihexylbut-2-ynediamide (7d)
Following the general procedure, workup A yielded 7d (0.94 g,
67%) as a colorless solid; mp 140 °C (CH2Cl2–PE).
Workup A: The mixture was partitioned between EtOAc and H2O
(100 mL each), and the organic layer was washed successively with
brine (100 mL), sat. NaHCO3 (100 mL), 1 M HCl (100 mL), and
brine (2 × 100 mL) [for compounds 7b,q,s–v,y brine was used in-
stead of H2O, and the organic phase was washed with brine (4 × 100
mL) only]. The solution was dried (MgSO4), the solvent was evap-
orated, and the residue was dissolved in a small amount of refluxing
THF. The major portion of 6-dimethoxy-1,3,5-triazin-2(1H)-one
(8) was crystallized at –20 °C, and the liquid phase containing the
product was separated and evaporated. The remaining residue was
further purified by column chromatography and/or recrystallization
as appropriate.
IR (KBr): 3295, 2960, 1628, 1309, 1276 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.15 (t, J = 5.7 Hz, 2 H), 3.36–3.24
(m, 4 H), 1.56–1.50 (m, 4 H), 1.36–1.27 (m, 12 H), 0.89 (t, J = 6.8
Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 151.80, 76.69, 40.13, 31.36,
28.94, 26.49, 22.50, 13.96.
HRMS (EI): m/z [M]+ calcd for C16H28N2O2: 280.2151; found:
280.2140.
Anal. Calcd for C16H28N2O2: C, 68.53; H, 10.06; N, 9.99. Found: C,
68.37; H, 9.83; N, 9.75.
Workup B: The mixture was poured into 1 M HCl (150 mL; for
compounds 7h,x H2O was used instead) with stirring at 0 °C, and
stirring was continued for 15 min. The resulting solid was collected
by filtration, washed with H2O, and dried under vacuum. The resi-
due was dissolved in a small amount of refluxing THF and further
purified as described above, except for compounds 7f,g,o, which
were simply washed with CHCl3 (3 × 10 mL).
N1,N4-Diallylbut-2-ynediamide (7e)
Following the general procedure, workup A yielded 7e (0.60 g,
62%) as a colorless solid; mp 105 °C (CH2Cl2–PE) (Lit.5 103–
104 °C).
IR (KBr): 3274, 3054, 1636, 1538, 1282 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.44 (s, 2 H), 5.83–5.78 (m, 2 H),
5.24–5.15 (m, 4 H), 3.92– (m, 4 H).
13C NMR (126 MHz, CDCl3): δ = 151.70, 132.55, 117.22, 76.82,
42.31.
N1,N4-Diphenethylbut-2-ynediamide (7a)
Following the general procedure, workup B yielded 7a (1.17 g,
73%) as a colorless solid; mp 151 °C (CH2Cl2–PE).
IR (KBr): 3280, 3062, 2256, 1635, 1539 cm–1.
MS (EI): m/z = 192.1 [M]+.
1H NMR (500 MHz, CDCl3): δ = 7.40–7.16 (m, 10 H), 6.31 (t,
J = 6.8 Hz, 2 H), 3.59 (dt, J = 7.0, 6.8 Hz, 4 H), 2.86 (t, J = 7.0 Hz,
4 H).
13C NMR (125 MHz, CDCl3): δ = 151.70, 138.15, 128.74, 128.68,
126.73, 76.69, 41.21, 34.93.
HRMS (EI): m/z [M]+ calcd for C20H20N2O2: 320.1525; found:
320.1527.
Anal. Calcd for C10H12N2O2: C, 62.49; H, 6.29; N, 14.57. Found: C,
62.21; H, 6.26; N, 14.52.
N1,N4-Di(prop-2-ynyl)but-2-ynediamide (7f)
Following the general procedure, workup B yielded 7g (0.75 g,
80%) as a colorless solid; mp 151 °C (EtOH).
IR (KBr): 3288, 3043, 1633, 1528, 1280 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 9.50 (d, J = 5.4 Hz, 2 H), 3.94
(dd, J = 5.4, 2.2 Hz, 4 H), 3.16 (t, J = 2.2 Hz, 2 H).
Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C,
74.99; H, 6.24; N, 8.75.
13C NMR (125 MHz, DMSO-d6): δ = 150.92, 80.19, 77.03, 73.99,
28.73.
N1,N4-Dipropylbut-2-ynediamide (7b)
Following the general procedure, workup A yielded 7b (0.58 g,
59%) as a colorless solid; mp 149 °C (CH2Cl2–PE) (Lit.5 151–
153 °C).
MS (EI): m/z = 188.1 [M]+.
Anal. Calcd for C10H8N2O2: C, 63.82; H, 4.28; N, 14.89. Found: C,
63.47; H, 4.31; N, 14.60.
IR (KBr): 3296, 3059, 2971, 2874, 1636, 1548, 1319, 1288, 1153
cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.37 (t, J = 5.4 Hz, 2 H), 3.25 (dt,
J = 6.9, 5.4 Hz, 4 H), 1.58–1.54 (m, 4 H), 0.93 (t, J = 7.4 Hz, 6 H).
N1,N4-Dibenzylbut-2-ynediamide (7g)
Following the general procedure, workup B yielded 7g (1.05 g,
72%) as a colorless solid; mp 203 °C (EtOH) (Lit.5 204–205 °C).
IR (KBr): 3219, 3055, 2932, 1634, 1558 cm–1.
13C NMR (125 MHz, CDCl3): δ = 151.94, 76.79, 41.78, 22.26,
1H NMR (500 MHz, DMSO-d6): δ = 9.56 (t, J = 6.0 Hz, 2 H), 7.36–
7-26 (m, 10 H), 4.35 (d, J = 6.0 Hz, 4 H).
11.27.
MS (EI): m/z = 195.1 [M]+.
© Georg Thieme Verlag Stuttgart · New York
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D. Heyl, W.-D. Fessner
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13C NMR (125 MHz, DMSO-d6): δ = 151.32, 138.64, 128.86,
127.83, 127.57, 77.32, 42.9.
HRMS (EI): m/z [M]+ calcd for C18H16N2O2: 292.1212; found:
292.1216.
N1,N4-Bis(4-methoxyphenyl)but-2-ynediamide (7l)
Following the general procedure, workup B yielded 7l (0.99 g,
61%) as a greenish solid; mp 210 °C dec. (MeOH).
IR (KBr): 3271, 1640, 1598, 1510, 1244 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 11.05 (s, 2 H), 7.55 (d, J = 8.9
Hz, 4 H), 6.92 (d, J = 8.9 Hz, 4 H), 3.73 (s, 6 H).
Anal. Calcd for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58. Found: C,
73.94; H, 5.46; N, 9.59.
13C NMR (75 MHz, DMSO-d6): δ = 156.59, 148.79, 131.52, 121.83,
114.51, 77.91, 55.67.
MS (EI): m/z = 324.3 [M]+.
N1,N4-Bis(1,3-benzodioxol-5-ylmethyl)but-2-ynediamide (7h)
Following the general procedure, workup B yielded 7h (1.27 g,
67%) as a pale yellow solid; mp 223 °C (MEK).
IR (KBr): 3263, 3071, 2898, 2785, 1850, 1630, 1551, 1493, 1466
cm–1.
Anal. Calcd for C18H16N2O4: C, 66.66; H, 4.97; N, 8.64. Found: C,
66.54; H, 4.95; N, 8.62.
1H NMR (500 MHz, DMSO-d6): δ = 9.46 (t, J = 6.0 Hz, 2 H), 6.86
(d, J = 7.9 Hz, 2 H), 6.82 (d, J = 1.4 Hz, 2 H), 6.74 (dd, J = 7.9, 1.4
Hz, 2 H), 5.99 (s, 4 H), 4.24 (d, J = 6.0 Hz, 4 H).
13C NMR (125 MHz, DMSO-d6): δ = 151.22, 147.74, 146.78,
132.46, 121.20, 108.54, 108.49, 101.37, 77.30, 42.75.
HRMS (EI): m/z [M]+ calcd for C20H16N2O6: 380.1008; found:
380.0996.
N1,N1,N4,N4-Tetrabutylbut-2-ynediamide (7m)
Following the general procedure, workup A yielded 7m (1.12 g,
67%) as a colorless oil.
IR (KBr): 3258, 2931, 2874, 1633 cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.51 (t, J = 7.4 Hz, 2 H), 3.35 (t,
J = 7.6 Hz, 2 H), 1.62–1.48 (m, 4 H), 1.39–1.26 (m, 4 H), 0.94 (t,
J = 7.4 Hz, 3 H), 0.92 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 152.59, 80.86, 48.72, 44.51,
30.95, 29.32, 20.11, 19.84, 13.73, 13.72.
Anal. Calcd for C20H16N2O6: C, 63.16; H, 4.42; N, 7.37. Found: C,
62.93; H, 4.31; N, 7.36.
HRMS (EI): m/z [M]+ calcd for C20H36N2O2: 336.2777; found:
336.2734.
N1,N4-Dicyclohexylbut-2-ynediamide (7i)
Following the general procedure, workup B yielded 7i (0.94 g,
68%) as a colorless solid; mp 235 °C dec. (CH2Cl2–PE) (Lit.5 244–
245 °C).
Anal. Calcd for C20H36N2O2: C, 71.38; H, 10.78; N, 8.32. Found: C,
71.31; H, 10.61; N, 8.10.
IR (KBr): 3300, 2936, 2858, 1636, 1524, 1321 cm–1.
N1,N1,N4,N4-Tetrallylbut-2-ynediamide (7n)
Following the general procedure, workup A yielded 7n (0.712 g,
52%) as a colorless oil.
IR (KBr): 3084, 2985, 2926, 1634, 1416, 1247 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.97–5.58 (m, 4 H), 5.45–5.05 (m,
8 H), 4.13 (d, J = 5.6 Hz, 4 H), 4.01 (d, J = 6.0 Hz, 4 H).
13C NMR (125 MHz, CDCl3): δ = 152.47, 132.18, 131.49, 118.51,
1H NMR (500 MHz, DMSO-d6): δ = 8.89 (d, J = 7.9 Hz, 2 H), 3.71–
3.50 (m, 2 H), 1.83–1.62 (m, 8 H), 1.55 (dd, J = 9.3, 3.5 Hz, 2 H),
1.38–0.95 (m, 10 H).
13C NMR (125 MHz, DMSO-d6): δ = 150.40, 77.19, 48.70, 32.31,
25.47, 24.89.
MS (EI): m/z = 276.2 [M]+.
Anal. Calcd for C16H24N2O2: C, 69.53; H, 8.75; N, 10.14. Found: C,
69.72; H, 8.59; N, 10.02.
118.48, 80.43, 50.52, 46.55.
MS (EI): m/z = 272.1 [M]+.
N1,N4-Bis[(R)-1-phenylethyl]but-2-ynediamide (7j)
Following the general procedure, workup B yielded 7j (1.12 g,
70%) as a colorless solid, which was recrystallized (CH2Cl2–PE);
mp 172 °C dec.
IR (KBr): 3297, 2937, 1640, 1527, 1270 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.66–7.12 (m, 12 H), 5.08 (m, 2
H), 1.49 (d, J = 6.9 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 150.76, 141.96, 128.72, 127.64,
126.19, 76.80, 49.77, 21.47.
MS (EI): m/z = 320.1 [M]+.
Anal. Calcd for C16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found: C,
70.24; H, 7.40; N, 10.15.
N1,N1,N4,N4-Tetrabenzylbut-2-ynediamide (7o)
Following the general procedure, workup B yielded 7o (1.63 g,
69%) as a colorless solid; mp 134 °C (EtOH).
IR (KBr): 3025, 2932, 1636, 1451, 1423 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 7.41–7.25 (m, 12 H), 7.24–
7.11 (m, 8 H), 4.59 (s, 4 H), 4.47 (s, 4 H).
13C NMR (125 MHz, DMSO-d6): δ = 152.81, 136.37, 136.30,
129.20, 129.05, 128.30, 128.19, 127.96, 127.58, 81.21, 51.80,
47.66.
HRMS (EI): m/z [M]+ calcd for C32H28N2O2: 472.2151; found:
472.2121.
Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C,
74.64; H, 6.28; N, 8.55.
N1,N4-Diphenylbut-2-ynediamide (7k)
Following the general procedure, workup A yielded 7k (0.71 g,
54%) as a pale yellow solid; mp 185 °C dec. (MeOH).
IR (KBr): 3280, 1641, 1527, 1445, 1325, 1264 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 11.21 (s, 2 H), 7.64 (d, J = 7.8
Hz, 4 H), 7.36 (dd, J = 7.8, 7.3 Hz, 4 H), 7.14 (d, J = 7.3 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 149.18, 138.37, 129.41, 125.14,
Anal. Calcd for C32H28N2O2: C, 81.33; H, 5.97; N, 5.93. Found: C,
80.97; H, 5.93; N, 5.87.
1,4-Di(pyrrolidin-1-yl)but-2-yne-1,4-dione (7q)
Following the general procedure, workup A yielded 7q (0.64 g,
58%) as a colorless solid; mp 118 °C (CH2Cl2–PE) (Lit.5 118–
119 °C).
IR (KBr): 2956, 2884, 1624, 1457, 1427 cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.65 (dd, J = 9.8, 3.7 Hz, 2 H),
3.47 (dd, J = 9.8, 3.7 Hz, 2 H), 1.95–1.90 (m, 4 H).
120.34, 77.89.
MS (EI): m/z = 264.3 [M]+.
Anal. Calcd for C16H12N2O2: C, 72.72; H, 4.58; N, 10.60. Found: C,
72.47; H, 4.59; N, 10.52.
13C NMR (125 MHz, CDCl3): δ = 150.73, 80.02, 48.07, 45.48,
25.27, 24.50.
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© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Acetylenedicarboxamides
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MS (EI): m/z = 220.2 [M]+.
IR (KBr): 3301, 3064, 2953, 1740, 1652, 1538, 1439, 1285 cm–1.
Anal. Calcd for C12H16N2O2: C, 65.43; H, 7.32; N, 12.72. Found: C,
65.24; H, 7.28; N, 12.53.
1H NMR (500 MHz, CDCl3): δ = 7.82 (d, J = 7.7 Hz, 2 H), 7.42–
7.33 (m, 10 H), 5.71 (d, J = 7.7 Hz, 2 H), 3.76 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 170.68, 150.67, 135.10, 129.11,
128.91, 127.37, 76.93, 56.65, 53.11.
HRMS (EI): m/z [M]+ calcd for C22H20N2O6: 408.1321; found:
N1,N4-Dibenzyl-N1,N4-dimethylbut-2-ynediamide (7r)
Following the general procedure, workup B yielded 7r (1.01 g,
63%) as a colorless solid; mp 127 °C (CH2Cl2–PE).
IR (KBr): 1634, 1404, 1239 cm–1.
408.1344.
1H NMR (500 MHz, CDCl3): δ = 7.40–7.15 (m, 10 H), 4.80, 4.73,
4.64 and 4.61 (4 s, 4 H), 3.16, 3.08, 2.93 and 2.91 (4 s, 6 H).
Anal. Calcd for C22H20N2O6: C, 64.70; H, 4.94; N, 6.86. Found: C,
64.64; H, 4.93; N, 6.71.
13C NMR (125 MHz, CDCl3): δ = 152.90, 152.81, 152.77, 152.67,
135.58, 135.44, 135.33, 128.96, 128.93, 128.79, 128.26, 128.15,
128.09, 127.89, 127.37, 127.28, 81.39, 81.34, 81.02, 80.89, 54.80,
54.69, 50.02, 35.77, 35.62, 32.10, 32.06.
N1,N4-Bis[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]-N1,N4-di-
methylbut-2-ynediamide (7w)
Following the general procedure, workup B yielded 7w (1.33 g,
65%) as a colorless solid; mp 82 °C (CH2Cl2–PE).
IR (KBr): 3420, 2938, 1622, 1404 cm–1.
MS (EI): m/z = 320.1 [M]+.
1H NMR (500 MHz, CDCl3): δ = 7.41–7.20 (m, 10 H), 4.94, 4.92,
4.73, and 4.77 (4 d, J = 8.0/8.0/7.9/6.3 Hz, resp., total 2 H), 4.61–
4.45 (m, 2 H), 3.33 (br s, 2 H), 3.09, 3.03, 2.86, and 2.86 (4 s, 6 H),
1.32, 1.27, 1.22, and 1.20 (4 d, J = 6.8/6.8/7.1/7.1 Hz, resp., total 6
H).
13C NMR (125 MHz, CDCl3): δ = 153.54, 152.93, 152.82, 141.45,
141.43, 141.15, 140.92, 128.51, 128.36, 128.11, 127.98, 127.75,
126.25, 126.06, 81.66, 81.51, 81.46, 81.38, 76.92, 76.61, 75.94,
59.96, 59.79, 56.90, 56.73, 34.05, 33.98, 28.75, 28.46, 13.53, 13.04,
11.03, 10.94.
Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C,
74.73; H, 6.25; N, 8.65.
Diethyl 2,2′-[(But-2-ynedioyl)bis(azanediyl)]diacetate (7s)
Following the general procedure, workup A yielded 7s (0.91 g,
64%) as a colorless solid; mp 121 °C (CH2Cl2–PE).
IR (KBr): 3378, 3289, 2992, 1756, 1659, 1527 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.55 (s, 2 H), 4.24 (q, J = 7.1 Hz,
4 H), 4.11 (d, J = 5.6 Hz, 4 H), 1.30 (t, J = 7.1 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 169.03, 151.74, 76.99, 61.92,
MS (EI): m/z = 408.2 [M]+.
41.50, 14.07.
MS (ESI): m/z = 307.2 [M + Na]+.
Anal. Calcd for C24H28N2O4: C, 70.57; H, 6.91; N, 6.86. Found: C,
70.37; H, 6.96; N, 6.68.
Anal. Calcd for C12H16N2O6: C, 50.70; H, 5.67; N, 9.85. Found: C,
50.85; H, 5.64; N, 9.97.
N1,N4-Bis{3-[5-(dimethylamino)naphthalene-1-sulfonami-
do]propyl}but-2-ynediamide (7x)
Following the general procedure, workup B yielded 7x (2.11 g,
61%) as a yellow solid; mp 97 °C (CH2Cl2–PE).
1H NMR (500 MHz, DMSO-d6): δ = 8.91 (t, J = 5.7 Hz, 2 H), 8.48
(d, J = 8.5 Hz, 2 H), 8.32 (d, J = 8.5 Hz, 2 H), 8.12 (dd, J = 7.1, 1.2
Hz, 2 H), 7.90 (t, J = 5.7 Hz, 2 H), 7.65–7.61 (m, 4 H), 7.27 (d,
J = 7.1 Hz, 2 H), 3.10–3.04 (m, 4 H), 2.84 (s, 12 H), 2.82–2.78 (m,
4 H), 1.58–1.51 (m, 4 H).
13C NMR (126 MHz, DMSO-d6): δ = 151.86, 151.22, 136.44,
129.88, 129.58, 128.66, 128.30, 124.03, 119.53, 115.59, 76.97,
45.53, 40.76, 37.10, 29.47.
Dimethyl 2,2′-[(But-2-ynedioyl)bis(azanediyl)]bis(4-methyl-
pentanoate) (7t)
Following the general procedure, workup A yielded 7t (1.30 g,
71%) as a colorless solid; mp 88 °C (CH2Cl2–PE).
IR (KBr): 3479, 3297, 2960, 1758, 1645, 1558 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.78 (d, J = 8.3 Hz, 2 H), 4.65 (dt,
J = 8.3, 5.4 Hz, 2 H,), 3.76 (s, 6 H), 1.87–1.55 (m, 6 H), 0.95 (d,
J = 6.4 Hz, 6 H), 0.94 (d, J = 6.4 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 173.26, 151.90, 77.37, 52.69,
51.34, 40.86, 24.93, 22.85, 21.74.
MS (ESI): m/z = 391.3 [M + Na]+.
MS (EI): m/z = 692.3 [M]+.
Anal. Calcd for C18H28N2O6: C, 58.68; H, 7.66; N, 7.60. Found: C,
58.39; H, 7.61; N, 7.51.
Anal. Calcd for C34H40N6O6S2: C, 58.94; H, 5.82; N, 12.13. Found:
C, 59.12; H, 5.68; N, 11.79.
Dimethyl 2,2′-[(But-2-ynedioyl)bis(azanediyl)]bis(3-phenylpro-
panoate) (7u)
Following the general procedure, workup A yielded 7u (1.42 g,
65%) as a colorless solid; mp 142 °C (CH2Cl2–PE).
N1,N4-Bis(N-{2-[(2,3,4,6-tetra-O-acetyl-β-D-galactopyrano-
syl)oxy]ethyl})but-2-ynediamide (7y)
Following the general procedure, workup A yielded 7y (2.54 g,
59%) as a colorless solid, which was recrystallized (CH2Cl2–PE);
mp 105 °C.
IR (KBr): 3301, 2953, 1740, 1652, 1538, 1439, 1285 cm–1.
IR (KBr): 3349, 2960, 1753, 1668, 1538, 1373, 1227 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.22 (m, 8 H), 7.20–7.13 (m,
4 H), 4.90 (td, J = 7.3, 5.7 Hz, 2 H), 3.76 (s, 6 H), 3.17 (d, J = 14.0,
5.7 Hz, 2 H), 3.06 (d, J = 14.0, 7.3 Hz, 2 H)
13C NMR (125 MHz, CDCl3): δ = 171.37, 151.21, 135.31, 129.17,
128.73, 127.34, 76.87, 53.91, 52.63, 37.52.
1H NMR (500 MHz, CDCl3): δ = 6.73 (t, J = 5.7 Hz, 2 H), 5.40 (dd,
J = 3.4, 1.0 Hz, 2 H), 5.22–5.15 (m, 2 H), 5.03 (dd, J = 10.3, 3.4 Hz,
2 H), 4.50 (d, J = 7.9 Hz, 2 H), 4.20 (dd, J = 11.3, 6.7 Hz, 2 H), 4.14
(dd, J = 11.3, 6.5 Hz, 2 H), 3.95 (dt, J = 6.6, 1.0 Hz, 2 H), 3.88 (ddd,
J = 10.3, 6.3, 4.0 Hz, 2 H), 3.76 (ddd, J = 10.3, 6.3, 4.0 Hz, 2 H),
3.58–3.45 (m, 4 H), 2.17 (s, 6 H), 2.09 (s, 6 H), 2.06 (s, 6 H), 1.99
(s, 6 H).
13C NMR (126 MHz, CDCl3): δ = 170.46, 170.13, 169.99, 169.69,
151.19, 101.30, 76.43, 70.91, 70.72, 68.75, 68.09, 66.97, 61.37,
39.73, 20.77, 20.63, 20.60, 20.50.
MS (ESI): m/z = 459.3 [M + Na]+.
Anal. Calcd for C24H24N2O6: C, 66.04; H, 5.54; N, 6.42. Found: C,
66.00; H, 5.51; N, 6.31.
Dimethyl 2,2′-[(but-2-ynedioyl)bis(azanediyl)]bis(2-phenylace-
tate) (7v)
Following the general procedure, workup B yielded 7v (1.51 g,
69%) as a colorless solid; mp 164 °C (CH2Cl2–PE).
MS (EI): m/z = 860.4 [M]+.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1463–1468

1468
D. Heyl, W.-D. Fessner
PAPER
(7) (a) Das, S.; Das, U.; Varela-Ramirez, A.; Lema, V.;
Anal. Calcd for C36H48N2O22: C, 50.23; H, 5.62; N, 3.25. Found: C,
50.51; H, 5.95; N, 2.95.
Aguillera, R. J.; Balzarini, J.; De Clercq, E.; Dimmock, S.
G.; Gorecki, D. K. J.; Dimmock, J. R. ChemMedChem 2011,
10, 2011. (b) Das, S.; Das, U.; Sakagami, H.; Umemura, N.;
Iwamoto, S.; Matsuta, T.; Kawase, M.; Molnar, J.; Serly, J.;
Gorecki, D. K. J.; Dimmock, J. R. Eur. Med. Chem. 2012,
51, 193.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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Synthesis 2014, 46, 1463–1468
© Georg Thieme Verlag Stuttgart · New York