A New Synthesis of Imines via Grignard- and Cuprate Additions
Ben L. Feringa,* Johan F.G.A. Jansen
Department of Organic Chemistry, University of Groningen, Nijenborgh 16, NL-9747 AG Groningen, The Netherlands
Various imines and some amines were synthesized by the addition of
Grignard reagents, homo- and hetero-cuprates to N-silylated-, N-alkyl-
or N-arylformamides 1.
The addition reaction of organolithium and organomagnesium
reagents to N,N-disubstituted amides is a facile method for the
synthesis of aldehydes and ketones.1 –6 Especially N-methyl-N-
formylaminopyridine2 and N-formylpiperidine6 were shown to
formylate efficiently a wide variety of Grignard reagents. We
recently described that the reaction of aryllithium compounds
with N-trimethylsilyl-N-alkyl- or N-arylamides yields imines.7
We now wish to report the formation of imines from the
reaction of N-trimethylsilyl-N-alkyl- or N-arylformamides 1,
with Grignard reagents (Scheme A), and Homo- and Hetero-
cuprates (Scheme B). Thus the reaction of N-trimethylsilyl-
N-phenylformamide with 1.3 equivalents of isopropylmagne-
sium bromide at – 80°C in tetrahydrofuran gave imine 2
(R1 = isopropyl, R2 = phenyl) in 94 % yield. The result of the
new imine synthesis using various Grignard reagents and
homo- and hetero-cuprates are summarized in Tables 1 and 2,
respectively.8 Good to high yields of pure imines are obtained
formed, show that only one isomer with E-configuration is
present. The imines 2 were conveniently converted into second-
ary amines 3 when reduced with lithium aluminum hydride
(Table 1). Our results constitute a new general method for the
synthesis of aldimines as well as secondary amines upon
13C-NMR data for all aldimines
Table 1. Imines 2 from the Addition of Grignard Reagents to N-
Silylated Formamides and Amines 3 via LiAlH4 Reduction of
mp (°C) or
Molecular Formula or
Lit. mp (°C) or
a Isolated yield.
b No bp reported.
c Crude yield: > 95 %. Pure product could not be isolated due to fast
polymerization on distillation or during chromatography.
Table 2. Imines 2 and Amines 4 via the Addition of Organocuprates to 1
or Lit. bp (°C)/mbar
a See Table 3 for HRMS.
b Reduction of 2j with LiAlH4 gave N-butyl-N-pentyl amine in 68 % yield.
c Using 2.6 equiv. of n-BuLi and 0.02 equiv. of CuBr with a reaction time of 24 h.
March 1988 Papers
The products of the reaction of 1 with homo- and hetero-
cuprates9 depend on the substituent R2 (Scheme B). In contrast
with the formation of imines from N-trimethylsilyl-N-alkyl-
substituted formamides, it was found that the cuprate addition
to N-trimethylsilyl-N-aryl-substituted formamides results in the
formation of α,α-disubstituted-N-arylamines 4 (Table 2).
addition to 5 (in equilibrium with 1)10 or via N- to O-shift of
the trimethylsilyl group in intermediate 6. The isolation of an
α,β-unsaturated aldimine (product 2e) shows that imine forma-
tion from these intermediates takes place during aqueous work-
up, as α,β-unsaturated aldimines generally undergo rapid poly-
merization in the presence of Grignard reagents.11 The absence
of amines 4 when Grignard or organolithium reagents are
used, even in excess, provides additional evidence that imines
are not formed prior to work-up. Because only a catalytic
amount of cuprous bromide is sufficient for the formation of
amines 4 (product 2b and 4b), when R2 is aryl, we propose that
the combined effect of a Cu+ counterion and a N-aryl-
substituent causes the elimination of copper(I) trimethylsilano-
late presumably from intermediate 7. Subsequent alkylation of
the imine 2 obtained in this way results in the formation of
Summarizing the results from Tables 1 and 2 it is shown that
aldimines and the corresponding amines can be synthesized in
good yields from alkyl and aryl-Grignard reagents. Further-
more, they can be obtained from aryllithium compounds7 and
from alkyllithium compounds via the organocopper reagent.
The latter reaction has not been extensively studied yet. The
synthesis of α,α-disubstituted-amines was successful only for
N-trimethylsilyl-N-arylformamides so far.
All compounds were characterized by IR, 1H-, 13C-NMR and
MS data. For compound 2e, only IR and 1H-NMR data of the
crude product were obtained due to its sensitive nature. The
spectroscopic data for all new compounds are summarized in
It is conceivable that the formation of imines 2 and amines 4
takes place via addition of the organometallic reagent to N-
trimethylsilylformamide 1 to provide intermediate 6 (Scheme
C). Alternatively intermediate 7 can be formed either via
Table 3. Spectroscopic Data of New Compounds
All reactions were carried our in dried glasware under a nitrogen
atmosphere. THF was distilled over sodium (benzophenone) under
nitrogen. The trimethylsilylformamides were prepared according to
literature13,14 and used in situ. IR spectra were recorded on a P-Unicam
Sp-200; 1H- and 13C-NMR spectra were recorded on Hitachi Perkin
Elmer R24B and Nicolet NT-200 spectrometers. Mass spectra were
obtained on an AEI MS-902 spectrometer.
N-(2-Methylpropylidene)aniline (2c); Typical Procedure:
To a stirred solution of N-trimethylsilyl-N-phenylformamide (1.65 g,
10 mmol) in THF (50 mL) at –80°C is added a 2 N solution of
isopropylmagnesium bromide in THF (6.5 mL, 13 mmol). Subsequently
the temperature of the mixture is raised to room temperature over a
period of 3.5 h. The mixture is poured into water (150 mL) followed by
extraction with ether (3 × 50 mL). The organic solution is dried
(Na2SO4). The solvent is evaporated and the crude liquid product 2c
distilled under reduced pressure; yield: 1.34 g (94%); bp 48–
49°C/1.3 mbar (Lit.10 bp 95°C/24 mbar).
δ, J (Hz)
HRMS (m/z, M+)
2.0 (s, 3H); 5.4 (m, 1H); 5.6 (m,
1H); 7.4–6.5 (m, 5H); 8.0 (s, 1H)
0.7–1.9 (m, 14H); 2.1–2.5 (m, 2H);
2.3 (t, 2H, J = 6); 7.6 (t, 1H, J = 5)
0.7–1.9 (m, 7H); 2.1–2.5 (m, 2H);
4.7 (s, 2H); 7.2 (s, 5H); 7.7 (t, 1H,
J = 5)
0.8–1.0 (m, 6H); 1.7 (br s, 44H);
3.3–3.5 (m, 2H); 6.4–7.3 (m, 5H)
– – –
13.38 (q), 13.67 (q), 20.12 (t), 22.20 (t),
28.11 (t), 32.68 (t), 35.32 (t), 60.86 (t),
13.52 (q), 22.03 (t), 27.66 (t), 35.24 (t),
64.61 (t), 126.51 (d), 127.47 (d), 128.06
(d), 138.46 (s), 165.97 (d)
14.02 (q), 22.61 (t), 25.81 (t), 28.67 (t),
29.28 (t), 29.56 (t), 30.07 (t), 30.24 (t),
30.52 (t), 31.35 (t), 31.84 (t), 34.82 (t),
52.76 (d), 112.72 (d), 120.65 (d), 128.80
(d), 129.13 (s)
(6) Olah, G.A., Arvanaghi, M. Org. Synth. 1986, 64, 114.
(7) Feringa, B.L., Jansen, J.F.G.A. Tetrahedron Lett. 1986 27, 507.
(8) The imines 2b, 2c, 2d, 2f, 2k form dimers, see for example:
Emmerson, C.D., Rhode, N.G., Bellet, E.M. European Patent
Appl. EP 66 872 A1; C.A. 1983, 98, 13 8993.
Harrada, K. in: The Chemistry of the C=N Double Bond, Patai, S.
(ed.), John Wiley & Sons, New York, 1970, Chapter 6, p. 255.
Miller, W., Plochl, J., Sender, L. Ber. Dtsch. Chem. Ges. 1892, 25,
(9) For reviews of organocopper reagents, see:
Normant, J.F. Synthesis 1972, 63.
Ref. 4, Chapter 14.
Yamamoto, Y. Angew. Chem. 1986, 98, 945; Angew. Chem. Int. Ed.
Engl. 1986, 25, 947, and references cited therein.
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Yoder, C.H., Belber, A.D. J. Organomet. Chem. 1976, 114, 251.
Bassindale, A.R., Posner, T.B. J. Organomet. Chem. 1979, 175,
Golebiowski, L., Lasocki, Z. Bull. Acad. Pol. Sci. Ser. Sci. Chim.
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(12) Kharrasch, M.S., Reinmuth, O. Grignard reactions of non-metallic
substances, Prentice Hall, New York, 1954.
See also: Yamamoto, J. Angew. Chem. 1986, 98, 952; Angew.
Chem. Int. Ed. Engl. 1986, 25, 954.
(13) Schirawski, G., Wannagat, V. Monatsh. Chem. 1969, 100, 1901.
(14) Birkhofer, L., Ritter, A., Dichopp, H. Chem. Ber. 1963, 96, 1473.
(15) Hantzsch, A., Schwab, O. Ber. Dtsch. Chem. Ges. 1901, 34, 822.
(16) Friedjung, E., Mossler, G. Monatsh. Chem. 1901, 22, 460.
(17) Buschmann, E., Zeeh, B. Liebigs Ann. Chem. 1979, 10, 1585.
(18) Krimm, H. Chem. Ber. 1958, 91, 1057.
(19) Stein, C.W.C., Day, A.R. J. Am. Chem. Soc. 1942, 64, 2567.
(20) Juday, R., Adkins, H. J. Am. Chem. Soc. 1955, 77, 4559.
(21) Tafel, J., Pfeffermann, E. Ber. Dtsch. Chem. Ges. 1902, 35, 1513.
(22) Fukui, K., Inamoto, Y., Takase, S., Kitano, H. J. Chem. Soc.
Japan Ind. Chem. Sect. 1959, 62, 532; C.A. 1962, 57, 8466.
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(24) Rice, R.P., Kohn, E.J. J. Am. Chem. Soc. 1955, 77, 4052.
(25) Barluenga, J., Jimenez, C., Nayera, C., Yus, M. Synthesis 1981,
(26) Lofter, K. Ber. Dtsch. Chem. Ges. 1910, 43, 2035.
(27) Coleman, G.H. J. Am. Chem. Soc. 1933, 55, 3001.
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N-(sec-Butyl)aniline (3c); Typical Procedure
The above procedure with the same amount of starting materials is
followed, but the ether solution, after drying, is added to a solution of
LiAlH4 (1.50 g, 40 mmol) in THF (50 mL). The mixture is stirred at
reflux for 16 h. A shorter reflux period might be sufficient in some cases.
After cooling of the solution to room temperature 10 % aqueous KOH
(5 mL) is added. The mixture is stirred at reflux for 1 h, before being
cooled to room temperature and filtered with suction. Omitting this
KOH treatment results in 10 to 15 % lower yields. The salt residues are
extracted with ether (100 mL) under reflux for 1 h. This procedure is
repeated four times. The combined ether solutions are dried (MgSO4),
the solvent is evaporated and the resulting oily residue distilled to give
3c; yield: 1.21 g (81 %); bp 88–90°C/3 mbar (Lit17 bp 111.5–
Preparation of N-Butyl-homocuprate; Typical Procedure:
To a stirred solution of CuBr (1.86 g, 13 mmol) in THF (80 mL)
at -80°C is added a 1.6 N hexane solution of n-BuLi (41.6 mL,
26 mmol). This mixture is stirred for 1 h at –60°C and then used as
N-(5-Nonyl)aniline (4b); Typical Procedures:
Method A: N-trimethylsilyl-N-phenylformamide (1.65 g, 10 mmol) dis-
solved in THF (50 mL) is added at –80°C to a solution of bis(n-
butyl)lithiumcuprate (120 mL) in THF, hexane prepared as above. The
mixture is allowed to warm slowly to room temperature (2.5 up to 3 h). A
work-up as described for compound 2c is followed by distillation to
provide 4b as an oil; yield: 2.10 g (96%); bp 110–111°C/1.5 mbar (Lit25
bp 112–113°C/1.6 mbar).
M e t h o d B: To a stirred solution of N-trimethylsilyl-N-phenyl-
formamide (1.65 g, 10 mmol) at –80°C is added CuBr (0.04 g, 0.02
equiv) followed by a 1.9 N solution of n-C4H9MgBr (13.5 mL) in THF
(13.5 mL). Following the procedure described for Method A, 4b is
obtained pure on distillation; yield: 1.62 g (74 %).
Received: 16 February 1987; revised: 21 September 1987
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