Efficient synthesis of alkyl β-diketimines

Article abstract of DOI:10.1021/jo801691m

(Chemical Equation Presented) A general synthesis for the preparation of alkyl N,N′-β-diketimines has been developed. The method reported here demonstrates the use of dimethyl sulfate for conversion of enaminoketones to β-diketimines. The reaction can be performed without solvent, providing good yields.

Full text of DOI:10.1021/jo801691m

Efficient Synthesis of Alkyl ꢀ-Diketimines
Alexander Z. Bradley,* David L. Thorn,† and
Gerald V. Glover
FIGURE 1. Meerwein’s salt (1) and dimethyl sulfate (2).
DuPont Central Research and DeVelopment, Wilmington,
Delaware 19880-0500
SCHEME 1. Preparation of Alkyl ꢀ-Diketimines (5a-g)
under Solvent-Free Conditions
alexander.z.bradley@usa.dupont.com
ReceiVed August 06, 2008
A general synthesis for the preparation of alkyl N,N′-ꢀ-
diketimines has been developed. The method reported here
demonstrates the use of dimethyl sulfate for conversion of
enaminoketones to ꢀ-diketimines. The reaction can be
performed without solvent, providing good yields.
ferred to as Meerwein’s salt, is often used to convert 4 to 5.5
We found that commercial sources of triethyloxonium tetrafluo-
roborate were unreliable and produced a mixture of products.6
In our hands, Meerwein’s reagent provides favorable results only
when prepared immediately prior to use. Despite this improve-
ment, there still remained the need to replace triethyloxonium
tetrafluoroborate due to cost and potential safety issues.
Our focus shifted to identifying a suitable replacement.
Dimethyl sulfate (2) is a strong electrophile for activating
oxygen as a leaving group and has been used extensively in
commercial applications.7 Moreover, industrial use of dimeth-
ylsulfate for O-alkylation has been reported by our company.8
The difficulties associated with the conversion of 4 to 5 results
from the recalcitrant nature of enaminoketone 4, an extended
amide. Therefore, a highly reactive reagent such as dimethyl
sulfate was required.
Compound 4 is treated with dimethylsulfate and let stand at
ambient temperature. Unless the enaminoketone 4 is a solid,
there is no need for a solvent. The primary amine is then added
dropwise to the reaction flask. In the same pot, the resulting
salt is treated with a sodium methoxide solution to liberate
ꢀ-diketimine 5. Filtration and removal of methanol provides a
crude mixture of 5 and unreacted or restored 4. Residual volatile
amine byproduct are removed with the solvent under vacuum.
The desired compound is easily isolated by fractional distillation.
The overall yields of compounds 5b-g are between 72-87%
(Scheme 1). Compound 5a proved difficult to isolate, decom-
We present in this Note the synthesis of alkyl ꢀ-diketimine
compounds using dimethylsulfate. Our group required a general
and efficient synthesis of N,N′-dialkyl-ꢀ-diketimines for use as
ligands in electronic materials. These ꢀ-diketimine compounds
are versatile as ancillary ligands for organometallic or inorganic
compounds.1
There has been a revival of interest in ꢀ-diketimines in the
past several years.2 However, much of this work has been
accomplished using aryl ꢀ-diketimines. The corresponding aryl
ꢀ-diketimine is typically prepared under forcing conditions that
are not conducive to volatile primary alkyl amines.3 There have
been few reports regarding the synthesis of alkyl ꢀ-diketimines
since McGeachin’s publication over 40 years ago.4 Our focus
is to provide a new commercially viable route to alkyl
ꢀ-diketimines.
We desired conditions that would be safe, cost-effective, and
amenable to large scale production, consistent with electronic
grade materials. We describe the development and optimization
of this synthetic process. The alkyl ꢀ-diketimines 5a-g were
prepared in a straightforward manner.
During substitution of 2,4-pentanedione (3) using primary
alkyl amines, only the first condensation step proceeds at an
observable rate. In compound 4, conversion of the carbonyl to
an imino group requires the use of a strong Lewis acid.
Triethyloxonium tetrafluoroborate reagent (1), commonly re-
(5) (a) Meerwein, H. Org. Synth. 1966, 46, 113. (b) Merriman, G. In
Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley:
New York, 1995; Vol. 3, p 2132. (c) Perst, H. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 3, p 5105.
(6) The material obtained from commercial suppliers was discolored and gave
an unacceptable degree of variability.
† Current address: Los Alamos National Laboratory.
(1) (a) Bradley, A. Z.; Thorn, D. L. U.S. Patent 7,388,113, 2008. (b) Bradley,
A. Z.; Thompson, J. S.; Park, K.-H.; Marshall, W. J.; Dobbs, K. D. Organo-
metallics 2006, 25, 2712. (c) Park, K.-H.; Bradley, A. Z.; Thompson, J. S.;
Marshall, W. J. Inorg. Chem. 2006, 45, 8480.
(2) Bourget-Merle, L.; Lappert, M. F.; Severn, J. R. Chem. ReV. 2002, 102,
(7) Kirk, R. E. In Encyclopedia of Chemical Technology; Othmer, D. F.,
Ed.; Wiley: New York, 1983; Vol. 22, p 236.
3031.
(3) Holm, R. H.; Parks, J. E. Inorg. Chem. 1968, 7, 1408.
(4) McGeachin, S. G. Can. J. Chem. 1968, 46, 1903.
(8) (a) Bensen, R. E.; Cairns, T. L. J. Am. Chem. Soc. 1948, 70, 2115. (b)
Caprolactam reactivity parallels that of related open chain amides.
10.1021/jo801691m CCC: $40.75
Published on Web 10/10/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8673–8674 8673

A solution of NaOMe (12.8 g, 237 mmol) in MeOH (40 mL)
was added to the intermediate salt (vida supra), and the mixture
was stirred (1 h) at ambient temperature. The solvent was removed
in vacuo to give an oil that was extracted with pentane, filtered
and concentrated to give a crude yellow oil. The product, N,N′-
diethyl-2,4-pentanediketimine, was isolated by fractional distillation
posing during distillation. The starting material (4) can be
collected as the higher boiling fraction or recovered from the
still pot.
The need for new materials to facilitate future electronic
technology applications has created a challenging synthetic
opportunity. We have developed a scalable and cost-effective
synthesis of ꢀ-diketimine ligands. We have extended the use
of dimethylsulfate to the synthesis of N,N′-dialkyl-ꢀ-diketimines
and established a viable protocol for a cost-effective preparation,
allowing suitable quantities of material for product sampling
and testing. We have found that dimethyl sulfate reduces
variability, achieving consistent results in multiple batch runs
over the course of several years, thus controlling impurities and
eliminating wasteful batch processes. By using a variety of alkyl
amines, we have demonstrated the general use of this method
to prepare alkyl ꢀ-diketimine ligands.
1
to give a yellow oil (28.6 g, 72% yield). H NMR (C6D6): δ 11.4
(s br, 1H) 4.56 (s, 1H), 3.10 (q, 4H, J ) 7.1 Hz), 1.69 (s, 6H),
1.15 (t, 6H, J ) 7.1 Hz). 13C NMR (C6D6): δ 160.1, 94.9, 91.5,
19.5, 17.2.
N,N′-Diisobutyl-2,4-pentanediketimine (5e). A 250 mL round
bottom flask was charged with 4-(isobutylamino)-3-pentene-2-one
(36.9 g, 237 mmol) and dimethylsulfate (30.0 g, 237 mmol). The
reaction solution was stirred (5 min) and then allowed to stand
(without stirring) overnight. The yellow mixture became orange
and viscous. Isobutyl amine (18 g, 246 mmole) was added
(exothermic) with vigorous stirring via addition funnel. The solution
was stirred (1 h) until it solidified. The intermediate salt was not
isolated and was directly converted to the free amine.
A solution of NaOMe (12.8 g, 237 mmol) in MeOH (ca. 40 mL)
was added to the intermediate salt and stirred for 1 h. The solvent
was removed in vacuo to give an oil that was extracted with pentane,
filtered and concentrated to give a crude yellow oil. The product
was isolated by fractional distillation to give a yellow oil (35.4 g,
72% Yield). 1H NMR (C6D6): δ 11.4 (s br, 1H) 4.68 (s, 1H), 3.07
(d, 4H, J ) 6.5 Hz), 1.93 (m, 2H), 1.83 (s, 6H), 1.08 (d, 12H, J )
7.0 Hz). 13C NMR (C6D6): δ 160.3, 95.3, 55.3, 30.9, 21.3, 19.9.
Safety. Dimethylsulfate is safely used in many commercial
processes. See http://www.dupont.com/dms/ for more information.
Experimental Section
Two representative ꢀ-diketimine ligand preparations, demonstrat-
ing the use of primary amines, are given below. NMR spectra were
recorded and chemical shifts were reported in ppm by reference to
deuterated solvent. All of the ꢀ-diketimines in this work are known
compounds; their NMR spectra are consistent with the chemical
literature.1,2,4
N,N′-Diethyl-2,4-pentanediketimine (5b). A 250 mL round
bottom flask was charged with 4-(ethylamino)-3-pentene-2-one
(30.0 g, 237 mmol) and dimethylsulfate (30.0 g, 238 mmol). The
reaction solution was stirred and then allowed to stand (12 h) at
ambient temperature to give a viscous oil. A 2 M solution of
ethylamine in THF (150 mL) was added with vigorous stirring.
The solution was stirred (1 h) until it solidified. The intermediate
salt can be isolated or used directly.
Supporting Information Available: Proton NMR spectra
of compounds 5a-g. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO801691M
8674 J. Org. Chem. Vol. 73, No. 21, 2008