Straightforward synthesis of alkynyl imines via 1,2-elimination of α,α-dichloroketimines

Article abstract of DOI:10.1016/j.tetlet.2007.07.047

Alkylation of α,α-dichloroketimines at the α-position with benzyl bromides afforded β-arylated α,α-dichloroketimines in good yields. The latter imines could be easily transformed to the corresponding alkynyl imines, a synthetically important class of comp

Full text of DOI:10.1016/j.tetlet.2007.07.047

Tetrahedron Letters 48 (2007) 6535–6538
Straightforward synthesis of alkynyl imines via 1,2-elimination
of a,a-dichloroketimines
Sven Mangelinckx, Stijn Rooryck, Jan Jacobs and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
Received 25 June 2007; revised 3 July 2007; accepted 6 July 2007
Available online 12 July 2007
Abstract—Alkylation of a,a-dichloroketimines at the a-position with benzyl bromides afforded b-arylated a,a-dichloroketimines in
good yields. The latter imines could be easily transformed to the corresponding alkynyl imines, a synthetically important class of
compounds, via 1,2-elimination of HCl upon treatment with 2 equiv of sodium hydride in DMSO or potassium tert-butoxide in
THF.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Alkynyl imines represent an important class of function-
alized alkynes because of their applications in the synthe-
toward alkynyl imines have hardly been described. Reac-
tion of dianions of 1-arylenaminones with trimethylchlo-
rosilane leads to alkynyl imines in moderate yield via an
unexpected elimination.14 In the present report, an
efficient and straightforward synthesis of benzimidoyl-
substituted alkynes is described based on two 1,2-elimi-
nations of HCl from b-arylated a,a-dichloroketimines
formed via alkylation of imines derived from a,a-dichlo-
roacetophenone derivatives.
sis of
a broad range of biologically important
compounds. Reduction of the imino function provides
access to propargyl amines, which are active as mono-
amine oxidase inhibitors.1 N-Methylation to iminium
salts gives rise to reactive dienophiles for Diels–Alder
reactions.2 Cyclization reactions of alkynyl imines have
been used for the synthesis of pyrrolinones,3 pyrroles,4
2-pyridones,5 pyrazoles and pyrimidines,6 quinolines
and fused pyrrolines.7 Cyclization of the corresponding
alkynyl hydrazones has led to the synthesis of different
pyrazoles.8 Despite their synthetic importance, relatively
few methods to synthesize alkynyl imines have been
described. One important methodology involves metal-
catalyzed coupling reactions of imidoyl halides,2,6,9 or
C,N-diarylnitrones,10 or the palladium-catalyzed reac-
tion product of bromobenzene and tert-butyl isocya-
nide,11 with organometallic reagents derived from
1-alkynes. Alternatively, alkynyl imines have been
prepared via imination of the corresponding alkynyl
ketones.4,8d,12 An interesting report has also been made
on the condensation reaction of a-chloroacetophenone
O-methyloxime derivatives to furnish alkynyl oxime
ethers via a [2+2]-cycloreversion of an azacyclobutadi-
ene intermediate.13 Surprisingly, elimination reactions
Based on the reported formation of N-[1-(4-chloro-
phenyl)-3-phenyl-2-propyn-1-ylidene]ethylamine 3 via
elimination of a-chloro-b-mesyloxy imine 4 as a side-
reaction during the cyclization of N-ethyl-b-mesyloxy-
amine 1 to the corresponding 3,3-dichloroazetidine 2
(Scheme 1),15 it was envisaged that b-arylated imines
with two leaving groups in a-position are potential sub-
strates for the synthesis of benzimidoyl-substituted
alkynes.
a,a-Dichloroketimines 516 were deprotonated with lith-
ium diisopropylamide (LDA) in tetrahydrofuran at
0 ꢁC to give the corresponding 3,3-dichloro-1-azaallylic
anions, which reacted with benzyl bromides at À78 ꢁC.
After further reaction at room temperature for 24 h,
the b-arylated a,a-dichloro imines 6 could be isolated
(56–94% yield) as pure crystalline compounds after
recrystallization from methanol (Scheme 2, Table 1).17
All compounds 6 occurred exclusively as the E-isomer.
Keywords: Alkynyl imines; 3,3-Dichloro-1-azaallylic anions; 1,2-Elim-
ination; Alkynyl ketones.
*
Corresponding author. Tel.: +32 9 264 59 51; fax: +32 9 264 62 43;
e-mail: norbert.dekimpe@UGent.be
The reactivity of the b-arylated a,a-dichloro imines 6
was studied with different bases in different solvents.
Postdoctoral Fellow of the Research Foundation—Flanders (FWO).
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.047

6536
S. Mangelinckx et al. / Tetrahedron Letters 48 (2007) 6535–6538
3 equiv. K2CO3
DMSO
NH OMs
N
N
H
H
+
85 °C
48 h
Cl Cl
Cl Cl
Cl
Cl
Cl
1
2 (60%)
3 (22%)
- MsOH
N
OMs
- HCl
Cl
Cl
Ref. 15
4
Scheme 1.
1) 1.1 equiv. LDA
THF, 1 h
R1
R1
N
N
0 °C to -78 °C
Cl
2) 1.05 equiv. 4-R3C6H4CH2Br
THF, 24 h, -78 °C to r.t.
Cl Cl
6a-g (56-94%)
Cl
R2
R3
R2
5
Scheme 2.
Table 1. Synthesis of b-arylated a,a-dichloro imines 6 from a,a-
dichloro imines 5
Hydrolysis of alkynyl imines to the corresponding
alkynyl ketones has been described via aqueous acid
hydrolysis with oxalic acid20 or hydrochloric acid.1a
However, hydrolysis of imine 7f with 2 N oxalic acid
in aqueous diethyl ether afforded an intractable mixture
of compounds. Treatment of imines 7a and 7f with 2 N
hydrochloric acid in aqueous tetrahydrofuran resulted
in the formation of b-chloro-a,b-unsaturated ketones
8a,f,21 representatives of the synthetically useful class
of b-chlorovinyl ketones,22 due to the addition of hydro-
gen chloride to alkynyl ketones 9. The latter reaction is
analogous to the known reaction of alkynyl ketones
with hydrogen chloride.23 In contrast, alkynyl ketones
Imine 6
R1
R2
R3
Yielda (%)
6a
6b
6c
6d
6e
6f
iPr
iPr
iPr
iPr
iPr
iPr
cHex
H
Cl
H
H
Me
H
Cl
H
MeO
Me
H
86
94
74
76
72
86
56
H
H
6g
H
a Isolated yields after recrystallization from methanol.
No reaction was observed upon the treatment of imine
6a with sodium hydride in tetrahydrofuran at 50–
60 ꢁC for several hours or upon the reaction of imine
6f with LiCl/Li2CO3 in dimethylformamide at 70 ꢁC
for 4 h,18 or upon refluxing imine 6f in pyridine for
3 h. In contrast, the use of 2.2 equiv of dimsylsodium
in dimethyl sulfoxide afforded the desired alkynes 7, as
single isomers, via two consecutive 1,2-eliminations of
HCl in moderate to good yields after purification by col-
umn chromatography (Scheme 3, Table 2).19 The yield
of alkynes 7a and 7e could be improved by reacting
a,a-dichloroketimines 6a and 6e with 2.2 equiv of potas-
sium tert-butoxide in tetrahydrofuran at 50–60 ꢁC for
3 h (Table 2). Upon reaction with sodium methoxide,
2 N in methanol, at 55 ꢁC for 3 h only complex reaction
mixtures were isolated.
Table 2. Synthesis of alkynes 7 from dehydrochlorination of b-
arylated a,a-dichloro imines
6
with dimsylsodium in dimethyl
sulfoxide
Alkyne 7
R1
R2
R3
Yielda (%)
7a
7b
7c
7d
7e
7f
iPr
iPr
iPr
iPr
iPr
iPr
H
Cl
H
H
Me
H
Cl
H
MeO
Me
H
44 (85)b
62
73
56
68 (79)b
78
H
7g
cHex
H
H
76
a Isolated yields after column chromatography.
b Isolated yields after column chromatography from reaction with
2.2 equiv potassium tert-butoxide in tetrahydrofuran.
R1
N
R1
N
2.2 equiv. NaH
DMSO
Cl Cl
50-60 °C, 3 h
R2
R3
R2
R3
6
7a-g (44-78%)
Scheme 3.

S. Mangelinckx et al. / Tetrahedron Letters 48 (2007) 6535–6538
6537
O
N
10 equiv. 2N H2SO4
R2
THF/H2O 1/1
R2
R3
Δ, 6 h
R3
7
9a (53%)
9c (65%)
9e (68%)
1.5 equiv. 2N HCl
THF/H2O 1/1
14 h, r.t.
O
Cl
R2
R3
8a (61%)
8f (61%)
Scheme 4.
2006, 47, 1729–1731; (d) Bishop, B. C.; Brands, K. M. J.;
Gibb, A. D.; Kennedy, D. J. Synthesis 2004, 43–52.
9. (a) Faust, R.; Go¨belt, B. Tetrahedron Lett. 1997, 38, 8017–
8020; (b) Lin, S.-Y.; Sheng, H.-Y.; Huang, Y.-Z. Synthesis
1991, 235–236; (c) Schlegel, J.; Maas, G. Synthesis 1999,
100–106; (d) Kobayashi, T.; Sakakura, T.; Tanaka, M.
Tetrahedron Lett. 1985, 26, 3463–3466.
10. (a) Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org.
Chem. 1995, 60, 4999–5004; (b) Okuro, K.; Enna, M.;
Miura, M.; Nomura, M. J. Chem. Soc., Chem. Commun.
1993, 1107–1108.
9a,c,e were obtained as pure crystalline compounds
upon hydrolysis with 2 N sulfuric acid in aqueous tetra-
hydrofuran (Scheme 4).24
In conclusion, a short and efficient synthesis of diaryl-
substituted alkynyl imines, a class of versatile intermedi-
ates in the synthesis of nitrogen-containing compounds,
has been achieved based on an unreported double 1,2-
elimination strategy of b-aryl-a,a-dichloro imines
formed via alkylation of N-isopropyl- or N-cyclohexyl-
3,3-dichloro-1-azaallylic anions. This alkylation and
elimination strategy should be applicable toward the
synthesis of other N-substituted alkynyl imines as well.
11. Kosugi, M.; Ogata, T.; Tamura, H.; Sano, H.; Migita, T.
Chem. Lett. 1986, 1197–1200.
12. Margaretha, P.; Schro¨der, C.; Wolff, S.; Agosta, W. C. J.
Org. Chem. 1983, 48, 1925–1926.
13. Tsuritani, T.; Yagi, K.; Shinokubo, H.; Oshima, K.
Angew. Chem., Int. Ed. 2003, 42, 5613–5615.
14. Bartoli, G.; Cimarelli, C.; Palmieri, G.; Bosco, M.;
Dalpozzo, R. Tetrahedron Lett. 1991, 32, 7091–7092.
15. Aelterman, W.; De Kimpe, N.; Declercq, J.-P. J. Org.
Chem. 1998, 63, 6–11.
Acknowledgments
The authors are indebted to the FWO and Ghent
University (GOA) for financial support of this research.
´
16. (a) De Kimpe, N.; Verhe, R.; De Buyck, L.; Moe¨ns, L.;
Schamp, N. Synthesis 1982, 43–46; (b) De Kimpe, N.;
Sulmon, P.; Schamp, N. Angew. Chem. 1985, 97, 878–879;
(c) De Kimpe, N.; Sulmon, P.; Schamp, N. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 881–882; (d) De Kimpe, N.;
Coppens, W.; Welch, J.; De Corte, B. Synthesis 1990, 675–
677.
References and notes
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17. General procedure: To an ice-cooled solution of diisopro-
pylamine (0.97 g, 9.6 mmol) in dry THF (9 mL) was added
under a N2 atmosphere n-BuLi (3.8 mL, 2.5 M in hexane,
9.6 mmol) followed after 10 min by a solution of a,a-
dichloro imine 5 (8.7 mmol) in THF (9 mL). The reaction
was cooled over a period of 1 h to À78 ꢁC and then a
solution of benzyl bromide (9.1 mmol) in THF (9 mL) was
added dropwise. The mixture was stirred for 1 h at À78 ꢁC
and gradually warmed to room temperature for 24 h. The
reaction mixture was poured into aq. NaOH (0.5 N,
30 mL) and extracted with CH2Cl2 (3 · 15 mL). The
combined extracts were dried (MgSO4/K2CO3), filtered
and evaporated. The crude reaction mixture was purified
by recrystallization (MeOH) to afford the pure crystalline
imine 6 (56–94% yield). N-(2,2-dichloro-1,3-diphenylpro-
pylidene)propyl-2-amine 6f: 1H NMR (CDCl3, 300 MHz):
d = 1.11 (d, 6H, J = 6.05 Hz, (CH3)2), 3.27 (septet, 1H,
J = 6.2 Hz, CH(CH3)2), 3.98 (s, 2H, CH2), 7.14–7.50 (m,
10H, 10 · CHar); 13C NMR (CDCl3, 75 MHz): d = 23.3,
49.7, 53.5, 90.8, 127.2, 127.6, 127.8, 128.5, 128.6, 132.2,
134.2, 135.5, 165.0; IR (KBr, cmÀ1): m = 1645; MS (ES,
7. Sromek, A. W.; Rheingold, A. L.; Wink, D. J.; Gevorg-
yan, V. Synlett 2006, 2325–2328.
8. (a) Ukhin, L. Y.; Orlova, Z. I.; Tokarskaya, O. A. Dokl.
Akad. Nauk SSSR 1986, 288, 897–899; (b) Ukhin, L. Y.;
Orlova, Z. I.; Tokarskaya, O. A. Chem. Abstr. 1986, 106,
102150; (c) Dirat, O.; Clipson, A.; Elliot, J. M.; Garrett,
S.; Jones, A. B.; Reader, M.; Shaw, D. Tetrahedron Lett.

6538
S. Mangelinckx et al. / Tetrahedron Letters 48 (2007) 6535–6538
pos. mode): m/z (%): 320/22/24 (M+H+, 100).
20. (a) Marks, M. J.; Walborsky, H. M. J. Org. Chem. 1982,
47, 52–56; (b) Gamboni, G.; Theus, V.; Schinz, H. Helv.
Chim. Acta 1955, 38, 255–263.
Yield = 86%. Mp = 110.0–110.3 ꢁC. White crystals.
18. Forti, L.; Ghelfi, F.; Pagnoni, U. M. Tetrahedron Lett.
1995, 36, 3023–3026.
21. For described syntheses of ketones 8, see: (a) Doyle, M. P.;
Devia, A. H.; Bassett, K. E.; Terpstra, J. W.;
Mahapatro, S. N. J. Org. Chem. 1987, 52, 1619–1621;
(b) Ohmori, H.; Maeda, H.; Ueda, C.; Masui, M.
J. Chem. Soc., Chem. Commun. 1988, 874–875; (c)
Dike, S. Y.; Mahalingam, M. Synth. Commun. 1989, 19,
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hedron Lett. 1995, 36, 7287–7288; (e) Zhou, H.; Zeng, C.;
Ren, L.; Liao, W.; Huang, X. Synlett 2006, 3504–
3506.
19. General procedure: To sodium hydride (0.15 g, 6.2 mmol)
was added DMSO (6 mL) and the mixture was stirred for
20 min at room temperature to generate dimsylsodium.
Subsequently, a,a-dichloro imine 6 (2.82 mmol), dissolved
in DMSO (9 mL), was added dropwise at room temper-
ature. After completion of the addition, the mixture was
kept at 55 ꢁC for 3 h. After cooling, water (10 mL) was
added and the aqueous phase was extracted with CH2Cl2
(3 · 15 mL). The combined organic phases were washed
with brine (3 · 15 mL), dried (MgSO4) and after filtration
and evaporation of the solvent, the crude alkynyl imine 7
was obtained. Further purification was performed by
column chromatography on silica gel (petroleum ether/
EtOAc 99:1) to yield the pure compound 7 (44–78% yield).
N-(1,3-Diphenylprop-2-yn-1-ylidene)-2-methylethylamine
7f. 1H NMR (CDCl3, 300 MHz): d = 1.32 (d, 6H,
J = 6.33 Hz, (CH3)2), 4.33 (septet, 1H, J = 6.33 Hz,
CH(CH3)2), 7.37–7.44 (m, 6H, 6 · CHar), 7.56–7.61 (m,
2H, 2 · CHar), 8.04–8.09 (m, 2H, 2 · CHar); 13C NMR
(CDCl3, 75 MHz): d = 23.5, 56.3, 81.5, 97.5, 121.7, 127.5,
128.2, 128.6, 129.5, 130.2, 132.1, 137.9, 148.3; IR (NaCl,
cmÀ1): m = 2204, 1591; MS (ES, pos. mode): m/z (%): 248
(M+H+, 100). Yield = 78%. Rf = 0.35 (petroleum ether/
EtOAc 9:1). Colorless viscous oil.
22. Pohland, A. E.; Benson, W. R. Chem. Rev. 1966, 66, 161–
197.
23. Kroeger, J. W.; Sowa, F. J.; Nieuwland, J. A. J. Org.
Chem. 1936, 1, 163–169.
24. General procedure: To a solution of alkynyl imine 7
(0.72 mmol) in THF (3.6 mL) was added aq. H2SO4 (2 N,
3.6 mL, 7.2 mmol). The reaction mixture was stirred for
6 h under reflux. The reaction mixture was poured into
aq NaOH (0.5 N, 20 mL) and extracted with Et2O
(30 mL). The combined extracts were dried (MgSO4),
filtered and evaporated. The crude reaction mixture was
purified by recrystallization (MeOH) to afford the pure
crystalline alkynyl ketone 9 (53–68% yield). The spectral
data of ketones 9 were in full agreement with reported
data.8d