Copper-catalyzed highly efficient multicomponent reactions of terminal alkynes, acid chlorides, and carbodiimides: synthesis of functionalized propiolamidine derivatives

Article abstract of DOI:10.1002/adsc.200700333

Functionalized propiolamidine derivatives were prepared in good to excellent yields under very mild conditions via a copper-catalyzed multi-component reaction (MCR) of readily available terminal alkynes, acid chlorides and carbodiimides with the assistance of triethylamine. The mechanism of this MCR is postulated.

Full text of DOI:10.1002/adsc.200700333

COMMUNICATIONS
DOI: 10.1002/adsc.200700333
Copper-Catalyzed Highly Efficient Multicomponent Reactions of
Terminal Alkynes, Acid Chlorides, and Carbodiimides: Synthesis
of Functionalized Propiolamidine Derivatives
Xiaoliang Xu,a,* Jianrong Gao,a Dongping Cheng,b Jinghua Li,b Genrong Qiang,a
and Hongyun Guoa
a
College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310032, Peopleꢀs
Republic of China
Phone/fax: (+86)-571-8827-3814; e-mail: xuxiaoliang@zjut.edu.cn
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, Peopleꢀs Republic of China
b
Received: July 7, 2007; Published online: November 23, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Functionalized propiolamidine derivatives
were prepared in good to excellent yields under
very mild conditions via a copper-catalyzed multi-
component reaction (MCR) of readily available ter-
minal alkynes, acid chlorides and carbodiimides
with the assistance of triethylamine. The mechanism
of this MCR is postulated.
the literature, there was no report about the synthesis
of N-carbonylpropiolamidine derivatives. From these
points of view, the search for a synthesis of different
types of propiolamidine derivatives is still in demand.
The MCR (multicomponent reaction), offering an
efficient route to generate complex molecular frame-
works from simple and readily available substrates, is
a powerful tool in modern organic synthesis as well as
in the fields of combinatorial chemistry and drug dis-
covery.[7] Although little attention was paid to novel
MCRs in the second half of the last century, they
have naturally been developed as a rapidly evolving
research area and have attracted the attention of both
academic and industrial scientists in the last few
years. Among them, the transition metal-catalyzed
Keywords: acid chlorides; alkynes; carbodiimides;
copper; multicomponent reactions; propiolamidine
derivatives
Amidine derivatives, due to their unique chemical MCRs are of high importance since they have excel-
and structural properties, have received much atten- lent catalytic efficiency in most cases.[8] Recently we
tion over the past decades and found wide application developed an MCR of terminal alkynes, sulfonyl
in medicinal chemistry and synthetic chemistry. Ami- azides and carbodiimides for the synthesis of func-
dine derivatives possessing a wide range of biological tionalized 2-(sulfonylimino)-4-(alkylimino)azetidine
and pharmacological activities such as antidegenera- derivatives with copper(I) iodide as a catalyst.[9,10]
tive, anticancer, antiplatelet and antimicrobial activi- Herein we report a novel copper-catalyzed three-com-
ties have been reported in the literature.[1] They also ponent reaction between terminal alkynes, acid chlor-
act as serine protease inhibitors and nitric oxide syn- ides and carbodiimides to give functionalized propiol-
thase inhibitors.[2] On the other hand, substituted ami- amidine derivatives in good to excellent yields.
dines are useful intermediates in the synthesis of
At first, N,N’-diisopropylcarbodiimide 1a, phenyl-
many heterocyclic compounds[3] and metal com- acetylene 2a and acetyl chloride 3a were selected as
plexes.[4] In fact, although various amidines have been the model substrates (Table 1). Catalyzed by CuI, sev-
reported, little information concerning propiolami- eral bases and solvents were examined to set up a
dine derivatives could be found in the literature. The standard set of reaction conditions. When the reaction
catalytic addition of terminal alkynes to carbodi- was performed in CH2Cl2 in the presence of 2 equiva-
imides by half-sandwich rare earth metal complexes, lents of triethylamine at room temperature for 2 h, it
LiNACHTREUNG(SiMe3)2 or Ru clusters to give the propiolamidine was found that the desired product 4a was indeed ob-
derivatives was published in the past years.[5] Use of tained albeit in only 40% yield (Table 1, entry 1).
acetyllithium as a stoichiometric nucleophilic reagent Yields of the desired product can be improved to
was employed for the synthesis of propiolamidines, 66% when CHCl3 or diethyl ether was used as the
however, the yields were very low.[6] Upon checking solvent (Table 1, entries 2 and 3). Toluene was not a
Adv. Synth. Catal. 2008, 350, 61 – 64
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
61

Xiaoliang Xu et al.
COMMUNICATIONS
Table 1. CuI-catalyzed the three-component reaction of N,N’-diisopropylcarbodiimide, phenylacetylene and acetyl chloride.
Entry
Solvent
Base
Time [h]
Yield [%][a,b]
1
2
3
4
5
6
7
8
9
10
CH2Cl2
CHCl3
ether[d]
toluene
THF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
TEA[c]
TEA
TEA
TEA
TEA
TEA
TEA
K2CO3
pyridine
DMAP
2
2.5
5
4
4
2
6
2
2
40
66
66
44
78
81
80
33
18
<5
2
[a]
N,N’-Diisopropylcarbodiimide (1 mmol), phenylacetylene (1.2 mmol), acetyl chloride (1.2 mmol), base (2 mmol), and CuI
(0.1 mmol) in solvent (3 mL) for the indicated time at room temperature under a nitrogen atmosphere.
Isolated yields based on N,N’-diisopropylcarbodiimide.
Triethylamine.
Diethyl ether.
[b]
[c]
[d]
good choice here (Table 1, entry 4). It is encouraging strate, almost no corresponding product was obtained.
to find that the result was further improved using The failure may be ascribed to the weak nucleophili-
THF as solvent (Table 1, entry 5). However, an even city of nitrogens which were conjugated with a ben-
better result came from the use of CH3CN in the zene ring.
presence of triethylamine and 4a was obtained in
According to previous work[11,12] and on the basis of
81% yield (Table 1, entry 6). Prolonging the reaction the above results, a tentative mechanism is suggested
time (6 h) or use of 2 equivalents of pyridine, DMAP in Scheme 1. The carbodiimide 1 reacts with acid
or K2CO3 instead of triethylamine as the bases could chloride 3 to form N-acyliminium salt 5, and alkyne 2
not improve the result (Table 1, entries 7–10).
is immediately converted to the copper acetylide 4 in
It can be summarized from Table 1 that the combi- the presence of triethylamine with one equivalent of
nation of CuI, TEA and CH3CN was a most efficient triethylamine acid salts being released. Then the nu-
catalytic system to catalyze the MCR of N,N’-diiso- cleophilic attack of 4 on 5 gives the desired product 6
propylcarbodiimide, phenylacetylene and acetyl chlo- and liberates the copper catalyst to complete the cata-
ride. To explore the scope of this catalytic system, a lytic cycle.
variety of substrates was applied and the results are
shown in Table 2.
In conclusion, we have developed a copper-cata-
lyzed multicomponent coupling of carbodiimides, al-
Benzoyl chloride gave the corresponding function- kynes, and acid chlorides. This MCR provides an effi-
alized propiolamidine derivatives in good to excellent cient method to construct functionalized propiolami-
yields. Aliphatic acid chlorides, such as acetyl chlo- dine derivatives.
ride, propionyl chloride and phenoxyacetyl chloride
were also appropriate substrates. As far as the alkynes
were concerned, aromatic alkynes substituted at the
phenyl ring with Br, Me, Pr, Bu and MeO were all
converted into the corresponding products efficiently,
indicating no remarkable electronic effects in the re-
action. It is noteworthy that 1-hexyne and 1-heptyne,
two aliphatic alkynes, afforded the desired products in
good yields as well. Two kinds of carbodiimides, DCC
or DIC, can be used successfully for this reaction.
Nevertheless, when N,N’-diphenylcarbodiimide or N-
Experimental Section
General Procedure for the Synthesis of
Functionalized Propiolamidine Derivatives
A suspension of carbodiimide (1.0 mmol) and acid chloride
(1.2 mmol) was stirred for 10 min in a 10-mL two-necked
vial under a nitrogen atmosphere, using tap water to cool
the reaction vial. Then anhydrous acetonitrile (3 mL), tri-
ethylamine (0.28 mL, 2.0 mmol), CuI (19 mg, 0.1 mmol) and
phenyl-N’-n-butylcarbodiimide was used as the sub- alkyne (1.2 mmol) were added successively at room temper-
62
asc.wiley-vch.de
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 61 – 64

Synthesis of Functionalized Propiolamidine Derivatives
COMMUNICATIONS
Table 2. CuI-catalyzed synthesis of functionalized propiolamidine derivatives 4.
Entry
R1
R2
R3
Time [h]
Yield [%][a,b]
1
2
3
4
5
6
7
8
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
Ph
CH3
CH3
CH3CH2
PhOCH2
CH3
CH3
CH3
CH3
Ph
CH3
Ph
CH3
Ph
Ph
CH3CH2
PhOCH2
2
2
2
2
4
2
2
2
2
2
2
2
2
2
3
2
81, 4a
90, 4b
96, 4c
53, 4d
72, 4e
95, 4f
83, 4g
60, 4h
80, 4i
79, 4j
75, 4k
71, 4l
78, 4m
83, 4n
66, 4o
61, 4p
4-CH3OC6H4
Ph
Ph
CH3AHCRTE(UNG CH2)4
4-CH3C6H4
4-BrC6H4
CH
(CH2)3
9
4-CH3OC6H4
4-n-PrC6H4
Ph
10
11
12
13
14
15
16
Ph
4-CH3OC6H4
4-n-BuC6H4
CH
Ph
3A
[a]
N,N’-Dialkylcarbodiimide (1 mmol), alkyne (1.2 mmol), acid chloride (1.2 mmol), TEA (2 mmol), and CuI (0.1 mmol) in
CH3CN (3 mL) for the indicated time at room temperature under nitrogen atmosphere.
Isolated yields based on N,N’-dialkylcarbodiimides.
[b]
the corresponding functionalized propiolamidine derivatives.
For more details, see Supporting Information.
Acknowledgements
This work was financially supported by Zhejiang University
of Technology.
References
[1] a) A. Panico, P. Vicini, M. Incert, V. Cardile, B. Gentile,
G. Ronsisvalle, Il Farmaco 2002, 57, 671; b) P. Sienkie-
wich, K. Bielawski, A. Bielawska, J. Palka, Environ.
Toxicol. Pharmacol. 2005, 20, 118; c) A. Bielawska, K.
Bielawski, A. Muszynska, Il Farmaco 2004, 59, 111;
d) T. M. Sielecki, J. Liu, S. A. Mousa, A. L. Racanelli,
Scheme 1.
E. A. Hausner, R. R. Wexler, R. E. Olson, Bioorg.
Med. Chem. Lett. 2001, 11, 2201; e) C. E. Stephens, E.
Tanious, S. Kim, D. W. Wilson, W. A. Schell, J. R. Per-
fect, S. G. Franzblau, D. W. Boykin, J. Med. Chem.
2001, 44, 1741.
ature. The mixture was stirred for the indicated time in
Table 2 (detected by TLC). To the resultant mixture was
added water (15 mL) and the whole was extracted with
CH2Cl2 (3”30 mL). The combined organic phase was
washed with saturated NaHCO3 solution and then water.
Then it was dried over anhydrous MgSO4 and evaporated
under vacuum. The residue was purified on a silica gel
column with petroleum ether/ethyl acetate as eluent to give
[2] a) J. W. Liebeschuetz, S. D. Jones, P. J. Morgan, C. W.
Marray, A. D. Rimmer, J. M. E. Roscoe, B. Waszko-
wycz, P. M. Welsch, W. A. Wylie, S. C. Young, H.
Martin, J. Mahler, L. Brady, K. Wilkinson, J. Med.
Chem. 2002, 45, 1221; b) J. L. Collins, B. G. Shearer,
Adv. Synth. Catal. 2008, 350, 61 – 64
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
63

Xiaoliang Xu et al.
COMMUNICATIONS
J. A. Oplinger, S. Lee, E. P. Garvey, M. Salter, C.
Dufry, T. C. Burnette, E. S. Furtine, J. Med. Chem.
1998, 41, 2858.
Kyokaishi 1999, 57, 912; e) J. A. Marshall, L. M.
McNulty, Chemtracts 1997, 10, 50.
[9] X. L. Xu, D. P. Cheng, J. H. Li, H. Y. Guo, J. Yan, Org.
[3] W. Lin, H. Li, X. Ming and F. Seela, Org. Biomol.
Lett. 2007, 9, 1585.
Chem. 2005, 3, 1714.
[10] For the selected papers of Cu-catalyzed MCRs recently
published, see: a) L. Zhang, H. C. Malinakova, J. Org.
Chem. 2007, 72, 1484; b) F. Colombo, M. Benaglia, S.
Orlandi, F. Usuelli, J. Mol. Catal. A: Chem. 2006, 260,
128; c) B. S. Huang, X. Q. Yao, C. J. Li, Adv. Synth.
Catal. 2006, 348, 1528; d) A. Gheorghe, A. Matsuno, O.
Reiser, Adv. Synth. Catal. 2006, 348, 1016; e) L. Zhao,
C. J. Li, Chem. Asian J. 2006, 1, 203; f) T. Pirali, G. C.
Tron, J. P. Zhu, Org. Lett. 2006, 8, 4145; g) J. Margathe,
M. Shipman, S. C. Smith, Org. Lett. 2005, 7, 4987; h) P.
Appukkuttan, W. Dehaen, V. V. Fokin, E. Van der
Eycken, Org. Lett. 2004, 6, 4223; i) D. A. Black, B. A.
Arndtsen, J. Org. Chem. 2005, 70, 5133; j) G. Cuny, M.
Bois-choussy, J. P. Zhu, J. Am. Chem. Soc. 2004, 126,
14475; k) M. Kozuka, A. Inoue, T. Tsuchida, M.
Mitani, Synlett 2004, 2756; l) L. Shi, Y. Q. Tu, M. Wang,
F. M. Zhang, C. A. Fan, Org. Lett. 2004, 6, 1001; m) S.
Kamijo, T. Jin, Z. B. Huo, Y. Yamamoto, J. Org. Chem.
2004, 69, 2386; n) N. Gommermann, C. Koradin, K.
Polborn, P. Knochel, Angew. Chem. 2003, 115, 5941;
Angew. Chem. Int. Ed. 2003, 42, 5763.
[11] a) K. Hartke, Chem. Ber. 1966, 99, 3163; b) K. Hartke,
E. Palou, Chem. Ber. 1966, 99, 3155; c) E. Palou, K.
Hartke, Rev. Real. Acad. Cienc. Exactas, Fis. Natr.
Madrid, 1968, 62, 155; Chem. Abstr. 1968, 69, 58813;
d) W. T. Brady, R. A. Owens, J. Org. Chem. 1977, 42,
3220.
[12] The MCRs of imines, acid chlorides, and alkynes cata-
lyzed by a variety of reagents were reported, see:
a) C. M. Wei, C. J. Li, Lett. Org. Chem. 2005, 2, 410;
b) F. Colombo, M. Benaglia, S. Orlandi, F. Usuelli, G.
Celentano, J. Org. Chem. 2006, 71, 2064; c) D. A.
Black, B. A. Arndtsen, Org. Lett. 2004, 6, 1107; d) C.
Fischer, E. M. Carreira, Org. Lett. 2004, 6, 1497.
[4] For reviews of amidinate coordination chemistry, see:
a) P. J. Bailey, S. Pace, Coord. Chem. Rev. 2001, 214, 91;
b) J. Barker, M. Kilner, Coord. Chem. Rev. 1994, 133,
219; c) F. T. Edelmann, Coord. Chem. Rev. 1994, 137,
403. For a review of the neutral coordination behavior
of these species, see: M. P. Coles, Dalton Trans. 2006,
985.
[5] a) W. X. Zhang, M. Nishiura, Z. M. Hou, J. Am. Chem.
Soc. 2005, 127, 16788; b) T. G. Ong, J. S. OꢀBrien, I.
Korobkov, D. S. Richeson, Organometallics 2006, 25,
4728; c) G. F. Schmidt, G. Suess-Fink, J. Organomet.
Chem. 1988, 356, 207.
[6] G. Himbert, W. Schwickerath, Liebigs Ann. Chem.
1984, 85.
[7] For reviews, see: a) A. Dçmling, Chem. Rev. 2006, 106,
17; b) Multicomponent Reactions, (Eds.: J. Zhu, H. Bi-
enaymꢂ), Wiley-VCH, Weinheim, 2005; c) D. J.
Ramꢃn, M. Yus, Angew. Chem. 2005, 117, 1628;
Angew. Chem. Int. Ed. 2005, 44, 1602; d) V. Nair, C.
Rajesh, A. U. Vinod, S. Bindu, A. R. Sreekenth, L. Ba-
lagopal, Acc. Chem. Res. 2003, 36, 899; e) R. V. A.
Orru, M. de Greef, Synthesis 2003, 1471; f) G. Balme,
E. Bossharth, N. Monteiro, Eur. J. Org. Chem. 2003,
4101; g) A. Dçmling, I. Ugi, Angew. Chem. 2000, 112,
3300; Angew. Chem. Int. Ed. 2000, 39, 3168; h) H. Bi-
enaymꢂ, C. Hulme, G. Oddon, P. Schmitt, Chem. Eur. J.
2000, 3321; i) L. Weber, K. Illgen, M. Almstetter, Syn-
lett 1999, 366.
[8] For reviews, see: a) L. Chen, C. J. Li, Adv. Synth. Catal.
2006, 348, 1459; b) J. Montgomery, Angew. Chem. 2004,
116, 3980; Angew. Chem. Int. Ed. 2004, 30, 3890; c) S.
Ikeda, Kagaku to Kogyo (Tokyo) 2000, 53, 146; d) K.
Itoh, I. Matsuda, Y. Yamamoto, Yuki Gosei Kagaku
64
asc.wiley-vch.de
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 61 – 64