Selective synthesis of (Z)-2-enynyl-2-hydroxy-imidazolidine-4,5-diones via Cu(i)-mediated multicomponent coupling of terminal alkynes, carbodiimides and oxalyl chloride

Article abstract of DOI:10.1039/c4ob00185k

(Z)-2-Enynyl-2-hydroxy-imidazolidine-4,5-diones 2 are synthesized for the first time via Cu(i)-mediated (Z)-selective geminal coupling among two molecules of terminal alkynes, carbodiimides, and oxalyl chloride. Further transformation of 2a is performed to yield a highly functionalized spiro heterocyclic compound 5. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00185k

Volume 12 Number 21 7 June 2014 Pages 3313–3514
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
ISSN 1477-0520
COMMUNICATION
Wen-Xiong Zhang et al.
Selective synthesis of (Z)-2-enynyl-2-hydroxy-imidazolidine-4,5-diones
via Cu(I)-mediated multicomponent coupling of terminal alkynes,
carbodiimides and oxalyl chloride

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Selective synthesis of (Z)-2-enynyl-2-hydroxy-
imidazolidine-4,5-diones via Cu(I)-mediated
multicomponent coupling of terminal alkynes,
carbodiimides and oxalyl chloride†
Cite this: Org. Biomol. Chem., 2014,
12, 3336
Received 24th January 2014,
Accepted 17th March 2014
DOI: 10.1039/c4ob00185k
Fei Zhao,a Yuexing Li,a Yang Wang,a Wen-Xiong Zhang*a,b and Zhenfeng Xia
www.rsc.org/obc
(Z)-2-Enynyl-2-hydroxy-imidazolidine-4,5-diones 2 are synthesized
for the first time via Cu(I)-mediated (Z)-selective geminal coupling
among two molecules of terminal alkynes, carbodiimides, and
oxalyl chloride. Further transformation of 2a is performed to yield
a highly functionalized spiro heterocyclic compound 5.
Considerable efforts have been devoted to the dimerization of
terminal alkynes because it provides a straightforward method
to construct conjugated enynes, which are versatile building
blocks in organic synthesis and significant components in bio-
active molecules.1,2 However, highly selective formation of
conjugated enynes by dimerization remains limited due to
the competitive formation of three possible (E)-, (Z)-, and gem-
enyne isomers.1,2 As far as we are aware, the multicomponent
coupling3 via incorporating organic components into the well-
established dimerization of terminal alkynes has not been
reported. It is a major challenge because the deprotonation of
the final enyne-containing intermediate with a terminal alkyne
is a fast step or the reductive elimination of the final acetylide
intermediate is more favorable in two reported mechanisms
(Scheme 1). Another challenge is how to control the regio- and
stereoselectivity of the corresponding enynes.
(Z)-2-En-4-yn-1-ols ((Z)-enynols for short), as a class of
multifunctional organic skeletons, are of considerable interest
in modern organic synthesis because of their important appli-
cation in synthesis of O-containing heterocycles.4,5 Although
the synthesis of (Z)-enynols has received much attention,6–10
(Z)-enynols bearing a heteroatomic substituent at the C1 position
have not been reported because of the difficulty in introducing a
Scheme 1 Unexpected (Z)-selective geminal coupling of two terminal
alkynes, carbodiimides and oxalyl chloride.
heteroatom into the starting materials. Thus, a simple and
efficient method to synthesize heteroatom-incorporated
(Z)-enynols at the C1 position remains of great importance
to academia and to the pharmaceutical industry. Herein we
report our new discovery of Cu(I)-mediated multicomponent
coupling of two terminal alkynes, carbodiimides, and oxalyl
chloride to construct the novel (Z)-enynols bearing a hetero-
cyclic linker at the C1 position. In this process, the (Z)-selective
geminal coupling of two molecules of terminal alkynes is
found. Further transformation of (Z)-enynol was performed to
yield highly functionalized spiro heterocyclic compounds.
We have focused on carbodiimide-based multicomponent
reactions to construct some N-containing organic mole-
cules.11,12 Recently we have reported one-pot sequential reac-
tion of amines, carbodiimides, and oxalyl chloride to prepare
cyclic di-oxoguanidines. The 2,2-dichloroimidazoline-4,5-dione
intermediate 1a was isolated and characterized from the reac-
tion of N,N′-diisopropylcarbodiimide (DIC) and oxalyl chloride
(see the ESI† for its X-ray structure).12e,13 The connection of
four electronegative atoms in 1a made the C2 atom highly
electrophilic. So we envisioned whether two C–Cl bonds in 1a
could undergo the cross-coupling reactions with terminal
aBeijing National Laboratory for Molecular Sciences, and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking University, Beijing 100871, China. E-mail: wx_zhang@pku.edu.cn;
Fax: +86-10-62751708; Tel: +86-10-62759728
bState Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin,
300071, China
†Electronic supplementary information (ESI) available: Materials including
experimental procedures, NMR spectra of all new products and X-ray data for 1a
and 2d. CCDC 857965 and 959743. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4ob00185k
3336 | Org. Biomol. Chem., 2014, 12, 3336–3339
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
gen sources for the reaction. Because of the steric hindrance of
t
the tert-butyl group, BuNvCvNtBu gave 2c in a significantly
lower yield than other N,N′-dialkylcarbodiimides. As far as
terminal alkynes were concerned, the reaction was not affected
by the positions of the substituents at the phenyl ring of an
aromatic alkyne (2d–l). Electron-donating groups such as alkyl
(2d–f) and alkoxy groups (2k) and weak electron-withdrawing
groups such as halogens (2h–j) would give good yields. It was
noted that strong electron-withdrawing groups at the phenyl
ring of an aromatic alkyne would result in no product. Hetero-
cyclic terminal alkynes such as 3-ethynylthiophene gave the
desired product 2l in 65% isolated yield. The single crystal
structure of 2d clearly revealed the Z-configuration of the
alkene moiety (see the ESI† for its X-ray structure).16
These interesting and novel results intrigued us to explore
the reaction mechanism. A series of experiments were per-
formed. First, the necessity of iodide was investigated. Iodide
is usually considered to be a good nucleophile as well as a
good leaving group. To obtain the evidence of the iodo-substi-
tuted intermediate, the 1 : 1 mixture of 1a and NaI in THF-d8
was monitored by NMR spectroscopy. Both 1H and 13C NMR
spectra showed the formation of a new compound. The in situ
NMR spectra also showed that the ratio of 1a and 4a was
Scheme 2 Screening of reaction conditions.
Table 1 Formation of (Z)-enynolsa
1 : 0.18 and remained unchanged after
a long period
(ca. 7 days), indicating that there was an equilibrium between
them (see ESI† for details). 4a is proposed to be a monoiodo-
substituted intermediate. Therefore, 2,2-dichloroimidazoline-
4,5-dione was proposed to undergo a Cl–I exchange giving an
important intermediate (eqn (1)).
Next, the sources of the alkenyl hydrogen and hydroxyl
group in product 2 were explored. A series of isotopic labeling
experiments were carried out. The final reaction mixture of 1a
with phenylethyne was quenched with H218O to produce the
18O-labeling product 2a-18O. This result clearly showed that the
hydroxyl group in 2 should come from water (eqn (2)).
Deuterium labeling experiments were performed with phenyl-
acetylene-d1 and/or D2O. A single deuterium source gave the
deuterated product 2a-D with low proportion of deuterium
(eqn (3) and (4)). Only a combination of the two deuterium
sources could lead to a fully deuterated product (eqn (5)). The
results showed that the alkenyl proton should be from both
terminal alkynes and water.
a Byproducts 3 were formed in 5–10% yields.
alkynes to generate 1,4-diynes. However, it was found that, in
the presence of CuI and Et3N, a (Z)-2-enynyl-2-hydroxy-imid-
azolidine-4,5-dione 2a14 was observed via the coupling of 1a
with two molecules of phenylethynes followed by a byproduct
3a. The expected 1,4-diyne product was not observed
(Scheme 2). After various reaction conditions including reac-
tion temperature, reaction time, bases,15 and the metal salts,
such as CuCl, CuBr, CuI and PdCl2, were screened (see ESI†
for details), an optimal condition was found and the expected
2a was isolated in 70% yield (Scheme 2).
ð1Þ
With the optimized conditions in hand, we began to
explore the reaction scope. The representative results for the
formation of (Z)-enynols 2 are summarized in Table 1.
2,2-Dichloroimidazoline-4,5-diones 1 were generated in situ
from carbodiimides and oxalyl chloride. Carbodiimides
ð2Þ
i
t
(RNvCvNR, R = Pr, Cy, Bu) were tested as suitable nitro-
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 3336–3339 | 3337

View Article Online
Communication
Organic & Biomolecular Chemistry
cross-coupling reaction of 4 with A would give rise to the inter-
mediate B and regenerate CuI. The regenerated CuI would
participate in the next catalytic cycle. B then undergoes an
isomerization to form chloroallene C, or further protonation
by Et3NH+ to form C′. A Stephens–Castro coupling of C or C′
with A would form D or D′. D is quenched with water to give
the final product 2.
Further transformation of (Z)-enynol 2a was tested under
various conditions. A new spiro heterocyclic compound 5 was
synthesized by electrophilic cyclization of 2a with I2 in THF
solution with K3PO4 as a base, which showed the potential of
this synthetic strategy (eqn (6)).17
ð3Þ
ð4Þ
ð6Þ
ð5Þ
In conclusion, Cu(I)-mediated (Z)-selective geminal MCR
coupling among two molecules of terminal alkynes, carbodi-
imides, and oxalyl chloride is achieved for the first time to
afford (Z)-enynols bearing a heterocyclic linker at the C1 posi-
tion. (Z)-Enynol shows the potential application in the syn-
thesis of highly functionalized spiro heterocyclic compounds.
It is noted that the multicomponent coupling via incorporat-
ing organic components into the well-established dimerization
of terminal alkynes is realized for the first time. Further
investigations on their application are ongoing.
Based on the experimental results above, a plausible mech-
anism for the formation of 2 is proposed in Scheme 3. In the
presence of Et3N, the copper acetylide (A) is generated from
terminal alkynes and CuI/CuCl, releasing the chloride and
iodide anions simultaneously. The nucleophilic substitution
of 1 by iodide generates the intermediate 4. A Sonogashira type
Acknowledgements
This work was supported by the Natural Science Foundation of
China and the “973” program from the National Basic
Research Program of China (2011CB808601). We also thank a
reviewer of the manuscript for the valuable suggestions.
Notes and references
1 For reviews of dimerization of terminal alkynes, see:
(a) M. Nishiura and Z. Hou, Bull. Chem. Soc. Jpn., 2010, 83,
595; (b) P. Wessig and G. Müller, Chem. Rev., 2008, 108,
2051; (c) H. Katayama and F. Ozawa, Coord. Chem. Rev.,
2004, 248, 1703; (d) M. Nishiura and Z. Hou, J. Mol. Catal.
A: Chem., 2004, 213, 101; (e) V. Ritleng, C. Sirlin and
M. Pfeffer, Chem. Rev., 2002, 102, 1731; (f) Modern Acetylene
Chemistry, ed. P. J. Stang and F. Diederich, VCH, New York,
1995.
2 For selected examples of dimerization of terminal alkynes,
see: (a) C. Jahier, O. V. Zatolochnaya, N. V. Zvyagintsev,
V. P. Ananikov and V. Gevorgyan, Org. Lett., 2012, 14, 2846;
(b) A. Coniglio, M. Basssetti, S. E. García-Garrido and
J. Gimeno, Adv. Synth. Catal., 2012, 354, 148;
(c) C. Pasquini and M. Bassetti, Adv. Synth. Catal., 2010,
Scheme 3 A proposed mechanism.
3338 | Org. Biomol. Chem., 2014, 12, 3336–3339
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
352, 2405; (d) W. Weng, C. Guo, R. Çelenligil-Çetin,
B. M. Foxman and O. V. Ozerov, Chem. Commun., 2006,
197; (e) X. Chen, P. Xue, H. H. Y. Sung, I. D. Williams,
M. Peruzzini, C. Bianchini and G. Jia, Organometallics,
2005, 24, 4330; (f) K. Komeyama, T. Kawabata, K. Takehira
and K. Takaki, J. Org. Chem., 2005, 70, 7260; (g) S. Ogoshi,
8 (a) S. Guo, H. Zhang, F. Song and Y. Liu, Tetrahedron, 2007,
63, 2009; (b) Y. Liu, F. Song and L. Cong, J. Org. Chem.,
2005, 70, 6999; (c) Y. Liu, F. Song, Z. Song, M. Liu and
B. Yan, Org. Lett., 2005, 7, 5409.
9 S.-H. Wang, Y.-Q. Tu, P. Chen, X.-D. Hu, F.-M. Zhang and
A.-X. Wang, J. Org. Chem., 2006, 71, 4343.
M. Ueta, M.-a. Oka and H. Kurosawa, Chem. Commun., 10 (a) C. C. Schneider, H. Caldeira, B. M. Gay, D. F. Back and
2004, 2732; (h) M. Nishiura, Z. Hou, Y. Wakatsuki,
T. Yamaki and T. Miyamoto, J. Am. Chem. Soc., 2003, 125,
1184; (i) A. Haskel, J. Q. Wang, T. Straub, T. G. Neyroud and
G. Zeni, Org. Lett., 2010, 12, 936; (b) Z. Lu and S. Ma, Adv.
Synth. Catal., 2007, 349, 1225; (c) Z. Lu and S. Ma, J. Org.
Chem., 2006, 71, 2655.
M. S. Eisen, J. Am. Chem. Soc., 1999, 121, 3025; 11 For selected reviews of carbodiimide chemistry, see:
( j) H. J. Heeres and J. H. Teuben, Organometallics, 1991, 10,
1980; Transition-metal catalyzed synthesis of enynes, also
see: (k) L. Zhou, F. Ye, J. Ma, Y. Zhang and J. Wang, Angew.
Chem., Int. Ed., 2011, 50, 3510; (l) F. Liu and D. Ma, J. Org.
Chem., 2007, 72, 4844.
(a) T. Suzuki, W.-X. Zhang, M. Nishiura and Z. Hou,
J. Synth. Org. Chem., Jpn., 2009, 67, 451; (b) H. Shen and
Z. Xie, J. Organomet. Chem., 2009, 694, 1652;
(c) W.-X. Zhang and Z. Hou, Org. Biomol. Chem., 2008, 6,
1720; (d) F. T. Edelmann, Adv. Organomet. Chem., 2008, 57,
183; (e) A. Williams and I. T. Ibrahim, Chem. Rev., 1981, 81,
589.
3 For reviews of MCRs: (a) B. B. Touré and D. G. Hall, Chem.
Rev., 2009, 109, 4439; (b) Multicomponent Reactions, ed.
J. Zhu and H. Bienayme, Wiley-VCH, Weinheim, Germany, 12 (a) Y. Wang, F. Zhao, Y. Zhou, Y. Chi, Z. Wang, W.-X. Zhang
2005; (c) J. Zhu, Eur. J. Org. Chem., 2003, 1133; (d) A. J. von
Wangelin, H. Neumann, D. Gördes, S. Klaus, D. Strübing
and M. Beller, Chem. – Eur. J., 2003, 9, 4286.
4 For reviews on application of enynols, see: (a) C. Fehr,
Synlett, 2012, 990; (b) R. C. D. Brown, Angew. Chem., Int.
Ed., 2005, 44, 850.
and Z. Xi, Chem. – Eur. J., 2013, 19, 10643; (b) Y. Wang,
Y. Chi, F. Zhao, W.-X. Zhang and Z. Xi, Synthesis, 2013, 347;
(c) Y. Wang, W.-X. Zhang, Z. Wang and Z. Xi, Angew. Chem.,
Int. Ed., 2011, 50, 8122; (d) Z. Wang, Y. Wang, W.-X. Zhang,
Z. Hou and Z. Xi, J. Am. Chem. Soc., 2009, 131, 15108;
(e) F. Zhao, Y. Wang, W.-X. Zhang and Z. Xi, Org. Biomol.
Chem., 2012, 10, 6266.
5 For recent progress on application of (Z)-enynols, see:
(a) H. Burghart-Stoll and R. Brückner, Org. Lett., 2011, 13, 13 For the first synthesis of 1a, see: (a) H. D. Stachel, Angew.
2730; (b) A. E. Díaz-Álvarez, P. Crochet and V. Cadierno,
Adv. Synth. Catal., 2010, 352, 2427; (c) F. Song and Y. Liu,
Chem., 1959, 71, 246; 1b and 1c: (b) G. Zinner and
R. Vollrath, Chem. Ber., 1970, 103, 766.
J. Organomet. Chem., 2009, 694, 502; (d) X. Du, F. Song, 14 For the first description of 2-hydroxy-imidazolidine-4,5-
Y. Lu, H. Chen and Y. Liu, Tetrahedron, 2009, 65, 1839;
(e) Y. Chen, Y. Lu, G. Li and Y. Liu, Org. Lett., 2009, 11,
dione, see: H. v. Pechmann and O. Ansel, Chem. Ber., 1900,
33, 1297.
3838; (f) L.-F. Yao and M. Shi, Eur. J. Org. Chem., 2009, 15 For a review on roles of bases in transition-metal catalyzed
4036; (g) X. Du, H. Chen and Y. Liu, Chem. – Eur. J., 2008,
14, 9495; (h) S. M. Abu Sohel, S.-H. Lin and R.-S. Liu,
coupling reactions, see: K. Ouyang and Z. Xi, Acta Chim.
Sin., 2013, 71, 13.
Synlett, 2008, 745; (i) H. Cao, W.-J. Xiao and H. Alper, 16 For X-ray structural proof of 2-hydroxy-imidazolidine-
J. Org. Chem., 2007, 72, 8562; ( j) H. Cao, W.-J. Xiao and
H. Alper, Adv. Synth. Catal., 2006, 348, 1807; (k) Y. Harrak,
C. Blaszykowski, M. Bernard, K. Cariou, E. Mainetti,
4,5-dione, see: A. Temeriusz, M. Rowińka, B. Piekarska-
Bartoszewicz, R. Anulewicz-Ostrowska and M. K. Cyrański,
J. Carbohydr. Chem., 2005, 24, 697.
V. Mouriès, A.-L. Dhimane, L. Fensterbank and 17 Similar reactions were performed by Liu and Larock, etc. In
M. Malacria, J. Am. Chem. Soc., 2004, 126, 8656;
(l) B. Gabriele, G. Salerno and E. Lauria, J. Org. Chem.,
1999, 64, 7687; (m) B. Gabriele, G. Salerno, F. De Pascali,
M. Costa and G. P. Chiusoli, J. Org. Chem., 1999, 64, 7693;
(n) B. Çetinkaya, B. Alici, I. Özdemir, C. Bruneau and
P. H. Dixneuf, J. Organomet. Chem., 1999, 575, 187.
both studies the Z-configuration of the exocyclic CvC
bond was confirmed by X-ray diffraction. In the presence of
I2 and a base, the electrophilic cyclization would first form
the E-configuration of the CvC bond, which isomerized
to the thermodynamically more stable Z-products in the
presence of I2. See: R. Mancuso, S. Mehta, B. Gabriele,
G. Salerno, W. S. Jenks and R. C. Larock, J. Org. Chem.,
2010, 75, 897. Also see: ref. 8b.
6 M. M. Midland, J. Org. Chem., 1975, 40, 2250.
7 J. A. Marshall and W. J. DuBay, J. Org. Chem., 1993, 58, 3435.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 3336–3339 | 3339