N -alkynyl imides (ynimides): Synthesis and use as a variant of highly labile ethynamine

Article abstract of DOI:10.1021/ol2014973

This study describes the first reliable synthesis of N-alkynyl imides (ynimides). This was accomplished with a copper-catalyzed coupling reaction between alkynyl(triaryl)bismuthonium salts and five-membered imides. We also found that it was possible to utilize N-ethynyl phthalimide as a variant of the highly labile ethynamine. 4-Amino-1,2,3-triazole was successfully obtained via the CuAAC reaction of N-ethynyl phthalimide with azide followed by hydrazinolysis of the phthaloyl protecting group.

Full text of DOI:10.1021/ol2014973

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3996–3999
N-Alkynyl Imides (Ynimides): Synthesis
and Use as a Variant of Highly Labile
Ethynamine
Takuya Sueda,* Ayumi Oshima, and Naoki Teno
Faculty of Pharmaceutical of Sciences, Hiroshima International University, 5-1-1
Hirokoshingai, Kure City, Hiroshima 737-0112, Japan
t-sueda@ps.hirokoku-u.ac.jp
Received June 5, 2011
ABSTRACT
This study describes the first reliable synthesis of N-alkynyl imides (ynimides). This was accomplished with a copper-catalyzed coupling reaction
between alkynyl(triaryl)bismuthonium salts and five-membered imides. We also found that it was possible to utilize N-ethynyl phthalimide as a
variant of the highly labile ethynamine. 4-Amino-1,2,3-triazole was successfully obtained via the CuAAC reaction of N-ethynyl phthalimide with
azide followed by hydrazinolysis of the phthaloyl protecting group.
Among the heteroatom-substituted alkynes, those with
nitrogen substitutions have become an important building
block in modern organic synthesis. The electronic bias
imposed by the nitrogen atom controls the stability and
reactivity of these alkynes. In general, ynamines that retain
the unsubstituted nitrogen atom are the most reactive of this
series; for example, ethynamine could not be isolated, be-
cause the equilibrium is shifted completely toward the more
stable acetonitriles.1 To overcome this unfavorable equili-
brium, a variety of ynamines have been developed.2 In most
cases, the stability of ynamines was increased by introducing
electron-withdrawing groups on the nitrogen atom or on the
triple bond.3 At present, special attention has been focused
on ynamides that are placed on an electron-withdrawing
carbonyl group on the nitrogen atom; these have set the
standard for balancing reactivity and stability.2c,3,4
In contrast to the well-defined ynamides, to date, there is
only one example of the production of an N-alkynyl imide
(ynimide) (Figure 1).5 Like ynamides, ynimides are also
considered to be stable and easy to handle, due to the two
carbonyl groups on the nitrogen atom. Furthermore,
imido groups are of great interest, because they are com-
mon fragments of many biologically active molecules, and
a traditionally reliable hydrazinolysis of the phthaloyl
group can lead to a free amino group. Herein, we report
the first reliable preparation of ynimides (3) in a copper-
catalyzed CꢀN coupling reaction between alkynylbis-
muthonium salts (1) and imides (2). Furthermore, we also
found that N-ethynyl phthalimide (3b) can be successfully
applied to the production of 4-amino-1-benzyl-1,2,3-triazole
(7) via a copper-promoted alkyneꢀazide cycloaddition
(1) Wentrup, C.; Briehl, H.; Lorencak, P.; Vogelbacher, U. J.;
Winter, H. W.; Maquestiau, A.; Flammang, R. J. Am. Chem. Soc.
1988, 110, 1337.
(2) For representative reviews on ynamines, see: (a) Witulski, B.;
Alayrac, C. Sci. Synth. 2006, 24, 1007. (b) Katritzky, A. R.; Jiang, R.;
Singh, S. K. Heterocycles 2004, 63, 1455. (c) Zificsak, C. A.; Mulder,
J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57,
7575. (d) Collard-Motte, J.; Janousek, Z. Top. Curr. Chem. 1986, 130,
89. (e) Ficini, J. Tetrahedron 1976, 32, 1449.
(3) For a special issue on the chemistry of electron-defficient yna-
mines and ynimides, see: Tetrahedron 2006, 62, 3771.
(4) For representative reviews on ynamides, see: (a) Dekorver, K. A.;
Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem.
Rev. 2010, 110, 5064. (b) Evano, G.; Coste, A.; Louvin, K. Angew.
Chem., Int. Ed. 2010, 49, 2840. (c) Witulski, B.; Alayrac, C. Sci. Synth.
2006, 24, 1031. (d) Tracey, M. R.; Hsung, R. P.; Antoline, J.; Kurtz,
K. C. M.; Shen, L.; Slafer, B. W.; Zhang, Y. Sci. Synth. 2005, 21, 387. (e)
Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379.
(5) The formation of 1-phenyl-2-(tetramethylsuccinimido)acetylene
(y. 5%) as side product from the reaction of 2-bromo-1-phenylacetylene
with N-tetramethylsuccinimide-tetrabutylammonium tetramethylsucci-
€
nimide complex has been reported, see: Eberson, L.; Lepisto, M.;
Finkelstein, M.; Hart, S. A.; Moore, W. M.; Ross, S. D. Acta Chem.
Scand. 1988, B42, 666.
r
10.1021/ol2014973
Published on Web 06/28/2011
2011 American Chemical Society

salt reactions with polyvalent bismuth compounds that
bear different hybridized carbon ligands, and (4) alkynyl-
bismuthonium salts would be expected to be formally
tetraphilic (acetylenic R- and β-carbon, arylic ipso-carbon,
and Bi atom) toward the attack of nucleophiles.
We initiated this study by examining the reaction be-
tween alkynyl(triphenyl)bismuthonium salt (1a) and suc-
cinimide (2a) in the presence of 30 mol % of CuBr and a
stoichiometric amount of Et3N in CH2Cl2. This resulted in
the formation of ynimide (3a), diyne (4), and N-aryl imide
(5a) (Table 1). Apparently, CuBr caused the cleavage of
both CalkynylꢀBi and CArꢀBi bonds, regardless of their
geometric positions.13 Lowering the reaction temperature
enhanced the selectivity of CalkynylꢀBi bond cleavage and
reduced the yield of the undesired 5a. Even at ꢀ40 °C, the
reaction proceeded to give 3a (48% yield) as a major
product, probably due to the high leaving ability of the
bismuthonio groups. We found that the distribution of
coupling products was also dramatically affected by the
solvent used in the reaction. Toluene, a nonpolar solvent,
favored the formation of N-aryl imide (5a). On the other
hand, with increasingly polar solvents, the cleavage of the
CalkynylꢀBi bond was enhanced, and in DMF, the pre-
dominant product was the homocoupled dimer (4). Con-
trol reactions carried out without Et3N or without CuBr
delivered no coupled products; this indicated that the base
and the copper catalyst were necessary for the coupling
reaction. In addition, no ynimide (3a) was obtained by
substituting Et3N with pyridine. Other copper salts, includ-
ing Cu(OAc)2, CuCl, or CuI, provided lower yields of 3a.
Figure 1. Ethynamine and its electron-deficient variants.
(CuAAC) followed by hydrazinolysis of the phthaloyl
protecting group.
In modern organic synthesis, transition-metal-catalyzed
coupling reactions are one of the most general procedures
for unsaturated carbonꢀnitrogen bond formation. Among
the transition metals, copper salts appear to be the most
effective in coupling with poorly nucleophilic nitrogen
sources such as amides and imides.6 As a carbon source, we
focused on the low toxicity of organobismuth compounds7
for use in copper-mediated CꢀN bond formation with
imides. These coupling reactions were developed by Barton
and Finet,8 and moreover, imide arylation and cyclopropa-
nation were successfully achieved by Chan9 and Gagnon,10
respectively. They combined the corresponding trivalent
organobismuth compounds with a stoichiometric amount
of copper salt. However, for the purpose of alkynylation,
trivalent alkynylbismuth compounds were considered trou-
blesome because of their low stability. Only alkynyl(diaryl)-
bismuth compounds are purely isolable, but they are difficult
to handle due to their marked tendency to hydrolyze.11 In
contrast to trivalent alkynylbismuth compounds, alkynyl-
(triphenyl)bismuthonium salts12 are relatively stable and
easy to handle in practical use. However, employing
alkynylbismuthonium salts as an alkynyl donor for the
coupling reaction was also considered to be very challen-
ging because (1) only four alkynylbismuthonium salts have
been synthesized,12 (2) therefore, very little is known about
their reactivities, (3) no information is available on copper
Table 1. Selected Screening Results for Copper-Catalyzed Re-
action of Alkynyl(triphenyl)bismuthonium Salt (1a) with Suc-
cinimide (2a)a
(6) For representative reviews on copper-mediated CꢀN bond for-
mation, see: (a) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008,
108, 3054–3131. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
2003, 42, 5400.
(7) Ge, R.; Sun, H. Acc. Chem. Res. 2007, 40, 267 and references
therein.
yield,c %
(8) For reviews on CꢀN bond-forming reactions using organobis-
muth compounds, see: (a) Finet, J.-P.; Pedonov, A. Y.; Combes, S.;
Boyer, G. Curr. Org. Chem. 2002, 6, 597. (b) Finet, J.-P. Chem. Rev.
1989, 89, 1487. (c) Abramovitch, R. A.; Barton, D. H. R.; Finet, J.-P.
Tetrahedron 1988, 44, 3039. (d) Barton, D. H. R.; Finet, J.-P. Pure Appl.
Chem. 1987, 59, 937.
ratioc
entry
solvent (εb)
temp
rt
3a
4
5a
(3aþ4):5a
1
2
3
4
5
6
7
8
CH2Cl2 (8.9)
CH2Cl2
34
48
50
48
3
5
59
37
27
25
87
83
48
0
40:60
56:44
73:27
71:29
4:96
0 °C
0
22
18
1
(9) Chan, D. M. T. Tetrahedron Lett. 1996, 37, 9013.
(10) Gagnon, A.; St-Onge, M.; Little, K.; Duplessis, M.; Barabe, F.
CH2Cl2
ꢀ20 °C
ꢀ40 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ20 °C
ꢀ
CH2Cl2
J. Am. Chem. Soc. 2007, 129, 44.
(11) (a) Rudolph, K.; Wieber, M. Z. Naturforsch. 1991, 46b, 1319. (b)
Hartmann, H.; Habenicht, G.; Reiss, W. Z. Anorg. Allg. Chem. 1962,
317, 54.
toluene (2.4)
Et2O (4.3)
THF (7.5)
DMF (38)
0
12
6
13:87
45:55
100:0
34
0
(12) Matano, Y. Chem. Commun. 2000, 2233.
79
(13) The bismuth center of alkynyl(triphenyl)bismuthonium tetra-
fluoroborate (1a) adopts a pseudotrigonal bipyramidal (TBPY) geome-
try with three phenyl ipso carbons at the equatorial sites and an
acetylenic carbon and fluorine atom at the apical sites. The TBPY
geometry is most probably maintained in solution, see ref 12.
a 1a (0.1 mmol), 2a (1.0 equiv), CuBr (30 mol %), and Et3N (1.0
equiv) for 5 h. b Dielectric constant. c Determined by 1H NMR.
Org. Lett., Vol. 13, No. 15, 2011
3997

Next, the para-substitutedalkynyl(triaryl)bismuthonium
salts (1aꢀ1d) were subjected to the coupling reaction
(Table 2). A Hammett plot was generated as follows: the
logarithm of the ratio of the product derived from CalkynylꢀBi
bond cleavage (3a þ 4) to N-aryl succinimide (5) was
plotted against the corresponding Hammett σ parameter
for each substituents (see Supporting Information). The
slope of the plot indicated that the CalkylꢀBi bond cleavage
was most favorable for aryl groups with electron-donating
substituents.
Table 3. Copper-Catalyzed CꢀN Coupling Reaction Using
Alkynyl(triaryl)bismuthonium Salts (1)a
A remaining problematic byproduct was the homo-
coupled diyne (4). This homocoupled dimer was probably
derived from the bis-alkynyl-Cu(III) intermediate. Stahl
previously investigated the copper-catalyzed aerobic oxi-
dativecoupling of terminal alkkynes and amides that led to
the formation of ynamides.14 On the basis of Stahl’s work,
the slow addition of an alkynyl source to the reaction
mixture could be expected to overcome the formation of 4.
For the practical simplicity, we chose to use excess equiva-
lents of imide. We found that 3.0 equiv of 2a was necessary
to obtain a meaningful yield of ynimide (3a); however, this
also slightly increased the yield of N-aryl succinimide (5)
(Table 2).
Table 2. Substituent Effects for Copper-Catalyzed Reaction of
Alkynyl(triaryl)bismuthonium Salt (1) with Succinimide (2a)
a 1 (0.1 mmol), 2 (3.0 equiv), CuBr (30 mol %), and Et3N (3.0 equiv) at
ꢀ40 °C for 5 h. b Isolated yield. c Determined by 1H NMR. d 6% of 1-(3,3-
dimethyl-2-oxobutyl)piperidine-2,6-dione was isolated. e 10 mmol of 1k
was employed.
salts (1) and a variety ofimides (2) (Table 3). Wefound that
aliphatic alkynyl groups coupled with five-membered imi-
des (2a, 2b, and 2c) gave moderate to good isolated yields.
Among these, the hindered alkynyl groups appeared to be
the most effective coupling partners. The reaction was also
compatible witha silyl-substituted group (entries 18and 19
used trimethylsilyl, 1k). Compared to alkynyl sources, the
2-phenylethynylbismuthonium salt gave a lower yield of 3
(entries 14 and 15). Although our coupling conditions were
not applicable to the N-ethynylation of imide (entry 1), we
could obtain N-ethynyl phthalimide (3b) via the protiode-
silylation of 3q (Scheme 2). Most ynamines that do not
have a substituent readily undergo hydrolysis or polymer-
ization; in contrast, 3b was stable in aqueous workups,
silica gels, heating, etc. and could be stored at room
temperature for several months. The six-membered and
acyclic imides (2d, 2e, and 2f) exhibited a lower acidity15
than that of five-membered 2a, 2b, and 2c compounds
and were not suitable for our N-alkynylation conditions
(entries 11ꢀ13).
equiv
yieldsa, %
ratioa
Ar (1)
2a
Et3N
3a
4
5
(3aþ4):5
p-MeOC6H4 (1b)
p-MeOC6H4 (1b)
p-MeOC6H4 (1b)
p-MeC6H4 (1c)
p-MeC6H4 (1c)
p-MeC6H4 (1c)
Ph (1a)
1
2
3
1
2
3
1
1
1
2
3
1
2
3
1
1
54
69
70
72
70
80
50
13
32
7
9 (5b)
14 (5b)
20 (5b)
17 (5c)
20 (5c)
18 (5c)
27 (5a)
66 (5d)
91:9
84:16
80:20
82:18
80:20
82:18
73:27
34:66
10
13
10
2
22
21
p-ClC6H4 (1d)
a Determined by 1H NMR.
The above findings suggested that the copper-catalyzed
reaction between alkynyl(triaryl)bismuthonium salts (1)
and several equivalents of imides (2) would lead to the
preferable formation of ynimides (3) when 1 contained an
electron-donating substituent on the aryl group and the
reaction conditions included a slightly polar solvent and a
low temperature. Subsequently, we investigated cross-
coupling reactions between various alkynylbismuthonium
To date, it is unclear what mechanisms underline the
copper-catalyzed coupling reaction between alkynyl(triaryl)-
bismuthonium salt (1) and imide nucleophiles (2). As
shown in Scheme 1, we offer a general proposal for the
(14) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130,
833.
(15) Breugst, M.; Tokuyasu, T.; Meyr, H. J. Org. Chem. 2010, 75,
5250.
3998
Org. Lett., Vol. 13, No. 15, 2011

Scheme 1. Plausible Reaction Mechanism for the Copper-Cat-
alyzed Coupling Reaction of Alkynyl(triaryl)bismuthonium
Salts (1) and Imides (2a)
Scheme 2. Copper-Mediated N-ethynylphthalimide-Azide Cy-
cloaddition and the Subsequent Hydrazinolysis of Phthaloyl
Protecting Group
(3b) was applied to the copper-mediated alkyneꢀazide
cycloaddition (CuAAC), and this provided a good yield
of 4-phthalimido-1-benzyl-1,2,3-triazole (6). Notably,
ynamides sometimes encounter drawbacks, for example,
hydrolysis under the CuAAC reaction conditions.18 How-
ever, 3b did not generate N-acetyl phthalimide generated
from its hydrolysis, even in the presence of 100 equiv of
H2O. Subsequent hydrazinolysis of the phthaloyl protect-
ing group on 6 afforded 4-amino-1-benzyl-1,2,3-triazole
(7).19 Thus N-ethynyl phthalimide (3b) can be utilized as a
variant of the highly labile ethynlamine.
In conclusion, we have developed a copper-catalyzed
coupling reaction between alkynyl(triaryl)bismuthonium
salts and imides. The reaction provided the first reliable
synthesis of ynimides. This reaction should expand the
scope of applications for nitrogen-substituted alkynes in
modern organic synthesis.
formation of the three coupling products formed from the
oxidative addition of Cu(I) to 1 and the subsequent reduc-
tive elimination.6b,16 When the alkynylbismuthonium salt
(1c) was reacted with 2a in the presence of (4-ClC6H4)3Bi
under the standard conditions, N-(4-chlorophenyl) succi-
nimide (5d) was not observed, and (4-ClC6H4)3Bi was
recovered quantitatively. This result suggested that no
equilibrium exists between the Cu(I) and Cu(III) species
shown in Scheme 1,17 On the basis of this finding and the
slope of the Hammett plot, we proposes that the product-
determining step occurs at the oxidative addition of Cu(I)
to alkynyl(triaryl)bismuthonium salt (1) and not at the
reductive elimination of the Cu(III) intermediate. As shown
in Scheme 1, the negative charges on the electron-donating
groups of the phenyl ring of 1 generate a repulsive force
during the oxidative addition process; this favors the
cleavage of the CalkynylꢀBi bond and affords the preferable
formation of the CalkynylꢀCu(III) intermediate.
Supporting Information Available. Synthesis of alkynyl-
(triaryl)bismuthonium salts, experimental details, and char-
acterization data for all new compounds.This material is
available free of charge via the Internet at http://pubs.acs.org.
Moreover, little N-ethynyl phthalimide (3b) was obtained
directly under the coupling conditions (Table 2, entry 1). This
inspired us to attempt the generation of copper acetylide
from ynimide. As shown in Scheme 2, N-ethynylphthalimide
(18) For CuAAC reaction of ynimides, see: (a) Kim, J. Y.; Kim, S. H.;
Chang, S. Tetrahedron Lett. 2008, 49, 1745. (b) Zhang, S.; Hsung, R. P.;
Li, H. Chem. Commun. 2007, 2420. (c) Zhang, X.; Li, H.; You, L.; Tang,
Y.; Hsung, R. P. Adv. Synth. Catal. 2006, 348, 2437. (d) Zhang, X.;
Hsung., R. P.; You, L. Org. Biomol. Chem. 2006, 4, 2679. (e) IJsselstijn,
M.; Cintrat, J.-C. Tetrahedron 2006, 62, 3837.
(19) For synthesis and characterization for 4-amino-3-benzyl-1,2,3-
triazole, see: Albert, A. J. Chem. Soc. C 1970, 230. The chemical shift of
1H NMR (in DMSO-d6) was not in agreement with that of 7 synthesized
in accordance with Scheme 2.
(16) Delp, S. A.; Goj, L. A.; Poay, M. J.; Munro-Leighton, C.; Lee,
J. P.; Gunnoe, T. B.; Cundari, T. R.; Petersen, J. L. Organometallics
2011, 30, 55.
(17) Our standard conditions (catalytic amount of CuBr at ꢀ40 °C)
applied to Ar3Bi did not afforded the corresponding N-aryl succinimide
at all.
Org. Lett., Vol. 13, No. 15, 2011
3999