Additive-free nucleophilic addition of imidazolines and imidazoles to haloacetylenes

Article abstract of DOI:10.1021/ol2027448

Nucleophilic addition of imidazolines to 1-halo-1-alkynes takes place by simple heating in DMF without any additives to give (Z)-N-(1-halo-1-alken-2-yl) imidazolines in good yield and in a highly regio- and stereoselective manner. These reaction condition

Full text of DOI:10.1021/ol2027448

ORGANIC
LETTERS
2012
Vol. 14, No. 1
34–37
Additive-Free Nucleophilic Addition of
Imidazolines and Imidazoles to
Haloacetylenes
Masahito Yamagishi,† Jun Okazaki,† Ken Nishigai, Takeshi Hata, and Hirokazu Urabe*
Department of Biomolecular Engineering, Graduate School of Bioscience and
Biotechnology, Tokyo Institute of Technology, 4259-B-59 Nagatsuta-cho, Midori-ku,
Yokohama, Kanagawa 226-8501, Japan
hurabe@bio.titech.ac.jp
Received October 13, 2011
ABSTRACT
Nucleophilic addition of imidazolines to 1-halo-1-alkynes takes place by simple heating in DMF without any additives to give (Z)-N-(1-halo-1-alken-2-yl)-
imidazolines in good yield and in a highly regio- and stereoselective manner. These reaction conditions are also valid for the similar addition
of imidazoles.
Nucleophilic addition to an electron-deficient carbonÀ
carbon multiple bond is one of the most fundamental
reactions in organic chemistry.1 While various potential
Scheme 2. Addition of Imidazolines to Haloacetylenes
electron-withdrawing groups (EWGs) adjacent to olefin
or acetylene are utilized for this process, the weakest
possible substituents, such as halogens, are also a subject
of interest, as shown in Scheme 1.2À4 Recent studies
along this line revealed that certain nucleophiles undergo
addition to 1-halo-1-alkynes.5À7 However, these feasible
addition mechanism equivocal.7 To enhance the role of a
halide group as shown in Scheme 1, we report here that
imidazolines, frequently found as constituents of natu-
rally occurring products or artificial pharmaceuticals,8
undergo a nucleophilic addition to haloacetylenes, by
Scheme 1. Halogen as an EWG in Nucleophilic Addition
(2) For the reactions of fluoro- or polyhalo-substituted olefins and
acetylenes, see: (a) Chambers, R. D. Fluorine in Organic Chemistry;
Wiley: New York, 1973. (b) Tanimoto, S.; Taniyasu, R.; Takahashi, T.;
Miyake, T.; Okano, M. Bull. Chem. Soc. Jpn. 1976, 49, 1931–1936. (c)
Kende, A. S.; Fludzinski, P.; Hill, J. H.; Swenson, W.; Clardy, J. J. Am.
nucleophiles are still limited, and some of them require a
promoter such as transition metal catalysts, making the
Chem. Soc. 1984, 106, 3551–3562. (d) Moyano, A.; Charbonnier, F.;
Greene, A. E. J. Org. Chem. 1987, 52, 2919–2922. (e) Geary, L. M.;
Hultin, P. G. J. Org. Chem. 2010, 75, 6354–6371.
(3) For reviews on nucleophilic addition to haloacetylenes, see: (a)
Chambers, R. D.; James, S. R. In Comprehensive Organic Chemistry;
Barton, D., Ollis, W. D., Stoddart, J. F., Eds.; Pergamon Press: Oxford, 1979;
Vol. 1, pp 557À560. (b) Himbert, G. In Methoden der Organischen
Chemie (Houben-Weyl); Kropf, H., Schaumann, E., Eds.; Georg Thieme:
Stuttgart, 1993; Vol. E15, Part 3, pp 3319À3329.
† These authors contributed equally to this work.
(1) (a) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 5th
ed.; Springer: New York, 2007; Part B, pp 183À200. (b) Smith, M. B.;
March, J. March’s Advanced Organic Chemistry, 6th ed.; Wiley: New
Jersey, 2007; pp 1130À1132. (c) Comprehensive Organic Synthesis; Trost,
B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4.
r
10.1021/ol2027448
Published on Web 11/29/2011
2011 American Chemical Society

only heating in an appropriate solvent without any ad-
ditives (Scheme 2).
During our study on the reactions of haloacetylenes,5d,9
we found that imidazolines undergo facile nucleophilic ad-
dition to haloacetylenes. Table 1 summarizes fundamen-
tal data regarding the addition of methylimidazoline 4 to
various 1-halo-1-octynes (halo = Cl, Br, or I). Among
Table 2. Preparation of Various (Z)-(1-Bromo-2-alkenyl)im-
idazolinesa
Table 1. Fundamental Data for Nucleophilic Addition
haloacetylene
X
product
entry
4 (equiv)
yielda (%)
1
2
3
4
5
Cl
Br
I
1
2
3
2
2
2
5
6
7
6
6
75
2
84
41
2
Br
Br
1.5
1
[66]
[36]
a Isolated yield based on haloacetylene. Values in brackets were
determined by 1H NMR using an internal standard.
the three haloacetylenes 1À3 (entries 1À3), bromoacety-
lene 2 showed the best result, affording (Z)-1-bromo-2-
(4) For brief survey of synthetic utility of haloacetylenes, see: (a)
Miller, S. I.; Dickstein, J. I. Acc. Chem. Res. 1976, 9, 358–363. (b)
Trofimov, A.; Chernyak, N.; Gevorgyan, V. J. Am. Chem. Soc. 2008,
130, 13538–13539.
(5) For addition of hydride, see: (a) Zweifel, G.; Lewis, W.; On, H. P.
J. Am. Chem. Soc. 1979, 101, 5101–5102. Halides: (b) Tanaka, R.;
ꢀ
Zheng, S.-Q.; Kawaguchi, K.; Tanaka, T. J. Chem. Soc., Perkin Trans. 2
1980, 1714–1720. (c) Chen, Z.; Jiang, H.; Li, Y.; Qi, C. Chem. Commun.
2010, 46, 8049–8051. Sulfonamide: (d) Yamagishi, M.; Nishigai, K.;
Hata, T.; Urabe, H. Org. Lett. 2011, 13, 4873–4875. Addition of thiols
was mentioned as an intermediate in the reaction of 1,1-dibromoolefins
and a few nucleophiles: (e) Xu, H.; Gu, S.; Chen, W.; Li, D.; Dou, J.
J. Org. Chem. 2011, 76, 2448–2458.
(6) For intramolecular nucleophilic addition to haloacetylene, see the
followings. With amino group: (a) Elokhina, V. N.; Yaroshenko, T. I.;
Nakhmanovich, A. S.; Albanov, A. I. Russ. J. Org. Chem. 2006, 42,
1866–1867. (b) Elokhina, V. N.; Nakhmanovich, A. S.; Larina, L. I.;
Yaroshenko, T. I.; Amosova, S. V. Russ. J. Org. Chem. 2009, 45, 226–
228. With hydroxy group: (c) Grandjean, D.; Pale, P.; Chuche, J.
Tetrahedron Lett. 1992, 33, 4905–4908. (d) Nakhmanovich, A. S.;
Elokhina, V. N.; Larina, L. I.; Abramova, E. V.; Lopyrev, V. A. Russ.
J. Gen. Chem. 2005, 75, 437–439. (e) Miao, Z.; Xu, M.; Hoffmann, B.;
Bernet, B.; Vasella, A. Helv. Chim. Acta 2005, 88, 1885–1912.
(7) For transition-metal-catalyzed addition of nucleophiles to haloa-
cetylenes has been reported. Under Cu catalysis, see: (a) Das, B.; Reddy,
G. C.; Balasubramanyam, P.; Salvanna, N. Synthesis 2011, 816–820. (b)
Burley, G. A.; Davies, D. L.; Griffith, G. A.; Lee, M.; Singh, K. J. Org.
Chem. 2010, 75, 980–983. For a reaction that is proposed to involve Ag-
catalyzed addition, see: (c) Chen, Z.; Li, J.; Jiang, H.; Zhu, S.; Li, Y.; Qi,
C. Org. Lett. 2010, 12, 3262–3265. For intramolecular additions under
Au catalysis, see: (d) Buzas, A. K.; Istrate, F. M.; Gagosz, F. Tetrahedron
a The reactions were performed with bromoacetylene (1 equiv) and
imidazoline (2 equiv) in DMF at 150 °C for 2 h. b Isolated yield based
on haloacetylene. c Imidazoline (1.1 equiv) was used. d Combined yield
of regioisomers. e Racemic sample.
ꢀ
2009, 65, 1889–1901. (e) Harkat, H.; Dembele, A. Y.; Weibel, J.-M.;
Blanc, A.; Pale, P. Tetrahedron 2009, 65, 1871–1879. (f) Buzas, A.;
Gagosz, F. Org. Lett. 2006, 8, 515–518. For reviews on relevant metal-
mediated hydroamination of acetylenes, see: (g) Alonso, F.; Beletskaya,
I. P.; Yus, M. Chem. Rev. 2004, 104, 3079–3159. (h) Pohlki, F.; Doye, S.
Chem. Soc. Rev. 2003, 32, 104–114.
(1-imidazolinyl)-1-octene (6) in good yield and virtually
as a single olefinic isomer (entry 2). For these reactions,
Org. Lett., Vol. 14, No. 1, 2012
35

no particular additives are necessary, and simple heating
in DMF proved good enough as shown in eq 1.10 If
desired, chloro-derivative 5 can be prepared albeit in a
somewhat lower yield and iodo-derivative 7 in a moderate
yield (entries 1 and 3). In each case, other regio- and
stereoisomers were not detected in the crude reaction
mixture. The use of excess imidazoline (2 equiv to
haloacetylene) is preferable to afford good yields (entries
2 vs 4 and 5). As this reaction does not need any additives,
including transition metal salts, it is most likely categor-
ized as nucleophilic addition of imidazolines to an elec-
tron-deficient acetylenic bond.11
Table 3. Preparation of Various (Z)-(1-Bromo-2-alkenyl)im-
idazoles
Other products obtained by this method are summa-
rized in Table 2. Entries 2À6 show that the mild reaction
conditions allow the presence of various functional
groups, involving an unprotected hydroxy group, on
the side chain of bromoacetylenes 8À12. For a sub-
stituent at the 2-position of imidazoline, the more
sterically hindered ethyl and cyclohexyl groups in 13
and 14 are acceptable to give 26 and 27, respectively
(entries 7 and 8). When 2-arylimidazolines 15 and 16
were used in slight excess (1.1 equiv to 2) (entries 9 and
10), addition products 28 and 29 were obtained in yields
better than that of 2-alkylimidazoline 4 (cf. entry 5,
Table 1). Unsymmetrically substituted imidazoline 17
or 18 afforded a mixture of 1,2,4- and 1,2,5-trisubsti-
tuted imidazolines 30 or 31, respectively (entries 11 and
12), but their combined yields remain good to excellent.
Likewise, 2,4,5-trisubstituted symmetrical imidazoline
19 afforded 32 in good yield (entry 13). Besides the
above imidazolines, 1,4,5,6-tetrahydropyrimidine 20, a
six-membered analogue of imidazoline, also afforded
the desired product 33 in good yield (entry 14). The
exceptional simplicity of this reaction prompted us to
examine its extension to imidazoles, an aromatic ana-
logue of imidazoline. Although a couple of recent
reports already deal with the addition of imidazoles to
bromoacetylenes in the presence of copper catalysts,12
we disclose here our own findings that their addition,
in fact, proceeds under the additive-free conditions.
Table 3 summarizes these results obtained according to
eq 1, except the prolonged reaction period (24 h rather
a Isolated yields.
ꢀ
(8) For recent examples, see: (a) Guinchard, X.; Vallee, Y.; Denis,
J.-N. Org. Lett. 2007, 9, 3761–3764. (b) Kahlon, D. K.; Lansdell, T. A.;
Fisk, J. S.; Hupp, C. D.; Friebe, T. L.; Hovde, S.; Jones, A. D.; Dyer,
R. D.; Henry, R. W.; Tepe, J. J. J. Med. Chem. 2009, 52, 1302–1309. (c)
Giorgioni, G.; Ambrosini, D.; Vesprini, C.; Hudson, A.; Nasuti, C.; Di
Stefano, A.; Sozio, P.; Ciampi, O.; Costa, B.; Martini, C.; Carrieri, A.;
Carbonara, G.; Enzensperger, C.; Pigini, M. Bioorg. Med. Chem. 2010,
18, 7085–7091.
(9) (a) Fukudome, Y.; Naito, H.; Hata, T.; Urabe, H. J. Am. Chem.
Soc. 2008, 130, 1820–1821. (b) Hirano, S.; Fukudome, Y.; Tanaka, R.;
Sato, F.; Urabe, H. Tetrahedron 2006, 62, 3896–3916. (c) Hirano, S.;
Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6, 727–729.
(10) These reaction conditions have been optimized. Various bases as
additive did not show any beneficial influence.
(11) An alternative radical mechanism seems unlikely, as radical
inhibitors such as BHT or galvinoxyl did not suppress the progress of
the reaction.
(12) See refs 7a and 7b. The addition of imidazoles to 1,1-dibromoo-
lefins was also performed in the presence of TBAF (Bu4NF) as an
additive (ref 5e). Compatibility with the functional groups shown in
entries 2À4 of Table 3 has not been addressed in these copper- or TBAF-
mediated reactions.
than 2 h). As extra additives to promote the addition are
not necessary at all, the reaction conditions appear to
be mild enough to allow the presence of typical func-
tional groups such as olefin, hydroxy group, and
ketone on the side chain of bromoacetylenes 34À36,
affording desired products 44À46 in good yields
(entries 2À4). Other types of imidazoles 38À42 also
afforded the expected products 47À51 in good yields
(entries 5À9).
In conclusion, (Z)-N-(1-halo-1-alken-2-yl)imidazolines
and (Z)-N-(1-bromo-1-alken-2-yl)imidazoles, versatile in-
termediates in organic synthesis yet otherwise tedious to
prepare, are conveniently synthesized by the nucleophilic
36
Org. Lett., Vol. 14, No. 1, 2012

addition of imidazolines or imidazoles to haloacety-
lenes. These reactions proceed under additive-free con-
ditions, with simple experimental operation, and in
good yield and with exclusive regio- and stereoselectiv-
ities. The compatibility with representative function-
al groups should be advantageous for practical appli-
cation of this method, which is underway in our
laboratory.
Acknowledgment. This work was supported by a
Grant-in-Aid for Challenging Exploratory Research
(22655014) from JSPS, Japan.
Supporting Information Available. Experimental pro-
cedures and spectroscopic properties for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 1, 2012
37