Synthesis of N,N-dimethylamines via Barbier-Grignard-type electrophilic amination

Article abstract of DOI:10.1080/00397910600770615

Aryl Grignard reagents react with N,N-dimethyl O-(mesitylenesulfonyl)- hydroxylamine in THF under Barbier conditions at room temperature and give N,Ndimethylanilines with high yields in a 2-h reaction. The amination yield of in situ Grignard reagents were not lower than those of preformed aryl Grignard reagents. In situ cycloalkyl-, allyl-, and benzylmagnesium bromides did not react with N,Ndimethyl O-(mesitylenesulfonyl)hydroxylamine, except that amination of in situ n-hexylmagnesium bromide resulted in a medium yield. Grignard-Barbier-type amination of aryl bromides with N,N-dimethyl O-(mesitylenesulfonyl)hydroxylamine provides a new alternative route for the synthesis of N,N-dimethylanilines. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600770615

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Synthesis of N,N‐Dimethylamines via
Barbier–Grignard‐Type Electrophilic
Amination
a
Ender Erdık a & Selma Ateş
a Department of Chemistry, Science Faculty , Ankara University , Ankara,
Turkey
Published online: 16 Feb 2007.
To cite this article: Ender Erdık & Selma Ateş (2006) Synthesis of N,N‐Dimethylamines via
Barbier–Grignard‐Type Electrophilic Amination, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:19, 2813-2818
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Synthetic Communicationsw, 36: 2813–2818, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600770615
Synthesis of N,N-Dimethylamines via
Barbier–Grignard-Type Electrophilic
Amination
Ender Erdık and Selma Ates¸
Department of Chemistry, Science Faculty, Ankara University,
Ankara, Turkey
Abstract: Aryl Grignard reagents react with N,N-dimethyl O-(mesitylenesulfonyl)-
hydroxylamine in THF under Barbier conditions at room temperature and give N,N-
dimethylanilines with high yields in a 2-h reaction. The amination yield of in situ
Grignard reagents were not lower than those of preformed aryl Grignard reagents. In
situ cycloalkyl-, allyl-, and benzylmagnesium bromides did not react with N,N-
dimethyl O-(mesitylenesulfonyl)hydroxylamine, except that amination of in situ
n-hexylmagnesium bromide resulted in a medium yield. Grignard–Barbier-type
amination of aryl bromides with N,N-dimethyl O-(mesitylenesulfonyl)hydroxylamine
provides a new alternative route for the synthesis of N,N-dimethylanilines.
Keywords: Barbier–Grignard reaction, electrophilic amination, N,N-dimethylani-
lines, tertiary amines
Amines constitute an important class of compounds in organic synthesis.[1] In
particular, arylamines have attracted much attention because of their subunit
character in the structure of various natural products and biologically active
compounds. Amines are generally prepared by nucleophilic amination, that
is, coupling of an electrophilic carbon with a nucleophilic aminating
reagent, NHꢀ2 .[2] Recently, Cu-catalyzed or mediated Ullman-type
Received in the U.K. December 17, 2005
Address correspondence to Ender Erdık, Department of Chemistry, Science
Faculty, Ankara University, Bes¸evler, Ankara 06100, Ankara, Turkey. E-mail:
erdik@science.ankara.edu.tr
2813

2814
E. Erdık and S. Ates¸
amination,[3] Pd-catalyzed Hartwig–Buchwald-type amination,[4,5] and
Ni-catalyzed amination[6] of aryl halides with amines provide convenient
and practical methods for the synthesis of arylamines. Another important
strategy is electrophilic amination, that is, coupling of carbanions with an
electrophilic aminating reagent, NHꢀ2 .[2,7–9] This type of umpolung
amination constitutes a potentially valuable method for transfer of an amino
group to carbanions[10–12] and enolates[13,14] to give amines and a-aminocar-
bonyl compounds, respectively. In addition, a successful asymmetric version
of electrophilic amination provides the most important and general methods
for the formation of chiral C22N bonds in stereomeric a-aminoacids.[13,14]
As NHꢀ2 synthons, a number of sp3N or sp2-containing reagents have been
extensively used for electrophilic amination. sp3-N-Type aminating reagents
react with carbanions directly (Scheme 1) to give primary amines[7–12] and
N-protected primary amines.[7–12,15] However, to date there have been a
limited number of reagents and methods to prepare secondary and tertiary
amines by electrophilic amination of carbanions.
Boche et al. used N,N-dialkyl O-(arenesulfonyl)hydroxylamines 2a,b
successfully for the amination of organolithiums and phenyl and a-naphthyl
Grignard reagents under mild conditions.[16] They also carried out
amination of cyclopentadienyllithium with 2c[17] and amination of lithium
1-alkynylcuprates with 3a with good yields.[18] Amination of diazapentalene
was also successful using 2a (R: Et).[19]
Johnson and Berman recently reported a general, convenient, and high-
yield method for the synthesis of tertiary amines by copper-catalyzed
amination of diorganozincs[20] and functionalized diarylzincs[21] and also
nickel-catalyzed amination of organozinc halides[22] with N,N-dialkyl
O-(benzoyl)hydroxylamines 4a,b.
We have previously shown Barbier conditions to be applicable to electro-
philic amination of Grignard reagents,[23] that is, we successfully carried out
the amination of in situ prepared arylmagnesium bromides with acetone
O-(2,4,6-trimethylphenylsulfonyl)oxime.[24]
Scheme 1. Electrophilic amination of organometallics with sp3N-type aminating
reagents.

Synthesis of N,N-Dimethylamines
2815
Scheme 2. Synthesis of N,N-dimethylamines by Barbier–Grignard-type amination.
Encouraged by these results, we examined 2a (R:Me) as aminating
reagent in our in situ protocol, which gives expeditious access to the
synthesis of tertiary amines. N,N-dialkyl O-(2,4,6-trimethylphenylsulfonyl)-
hydroxylamines 2a,b are easily prepared aminating reagents,[16] and prepre-
pared organolithiums and unsubstituted aryl Grignard reagents were
reported to have no practical problems in their amination with 2a or 2b.
However, amination of in situ prepared Grignard reagents is, by all means,
a less time-consuming procedure leading to fewer by-products.
Herein, we report a novel and efficient method for synthesis of N,N-
dimethylanilines by Barbier–Grignard-type electrophilic amination (Scheme 2).
We carried out a series of reactions to establish the optimum conditions
required for C–N coupling of in situ Grignard reagents with the Me2Nꢀ
synthon. High yields of N,N-dimethylanilines were obtained by simultaneous
Table 1. Amination of aryl Grignard reagents with N,N-
dimethyl O-(2,4,6-trimethylphenyl-sulfonyl) hydroxylamine
2a (R:Me) under Barbier conditionsa
Entry
Ar
C6H5 6a
Yield (%)b–d
1
2
3
4
5
6
81 (82)
79 (86)
83 (87)
60
4-MeC6H42 6b
3-MeC6H42 6c
2-MeC6H42 6d
4-MeOC6H42 6e
3-MeOC6H42 6f
80 (86)
78 (91)
aIn situ prepared ArMgBr reagent (3 equiv.) was aminated
with 2a (1 equiv.) at room temperature.
bYield of amine isolated after hydrolytic workup. The purity
of amines are at least 95% as judged by GC analysis.
cGC yields are given in parentheses.
dIsolated yields and GC yields are averages of at least two
reactions.

2816
E. Erdık and S. Ates¸
addition of 3 equiv. of aryl bromide and a THF solution of 1 equiv. of 2a
(R:Me) to 3.6 equiv. of Mg at room temperature and stirring the mixture at
this temperature for 2 h.
Phenyl- and a number of substituted phenylmagnesium bromides were
successfully aminated under Barbier conditions (Table 1). The yields are
not lower than those obtained with preprepared aryl Grignard reagents. For
example, amination of preprepared phenylmagnesium bromide with 2a
(R:Me) at room temperature gave 71% yield. (The reported[16] yield is
42%.) In comparison, amination of in situ prepared phenylmagnesium
bromide gave the product in 81% yield. However, trying to aminate in situ
prepared 3-bromophenylmagnesium bromide gave a mixture of products,
and amination of in situ prepared 4-(trifluoromethyl)phenylmagnesium
bromide resulted in 26% yield of product.
In our attempt to extend the Barbier–Grignard-type amination, n-hexyl-
magnesium bromide and benzylmagnesium bromide were reacted with 2a
(R:Me) using the in situ protocol. However, the results were less satisfactory
because we could get N,N-dimethyl n-hexylamine and N,N–dimethyl
benzylamine in only 54% and 10% isolated yields, respectively.
EXPERIMENTAL
Under a nitrogen atmosphere, an oven-dried three-necked flask equipped with
a reflux condenser, an addition funnel, and a magnetic stirring bar was charged
with magnesium (0.0864 g, 3.6 mmol). The reaction flask and magnesium was
flame dried, and the addition funnel was charged with 2a (R:Me) (0.2430 g,
1 mmol in 4 mL of THF). At room temperature, the reaction was started by
adding a few drops of aryl bromide (3 mmol) in a syringe. If necessary, the
flask was heated for a short time. While stirring, aryl bromide and a
solution of 2a were added simultaneously at a rate that does not stop the
reaction. (The use of aryl bromide without THF gave better results for the
in situ formation of arylmagnesium bromide.) Following the disappaerence
of magnesium, the reaction mixture was stirred at room temperature for 2 h.
For quantitative GC analysis of the reaction products, the reaction mixture
was hydrolyzed with a saturated NaHCO3 solution (10 mL) and the aqueous
layer was extracted with Et2O (2 ꢁ 10 mL). The combined organic layers
were dried over Na2SO4 and concentrated. For the isolation of an N,N-
dimethylaaniline, the ethereal solution of the product was washed with 1 M
conc. HCl solution (2 ꢁ 10 mL). The aqueous phase was basified with 10%
NaOH solution and extracted with Et2O (3 ꢁ 10 mL). The ethereal solution
was dried over Na2SO4 and concentrated to give N,N-dimethyl anilines.
The purity of oily N,N-dimethylanilines was found to be ꢂ95% by GC
analysis. Solid N,N-dimethylanilines were recrystallized. Melting points of
solid N,N-dimethylanilines and 1H NMR spectra of all ter-amines were

Synthesis of N,N-Dimethylamines
2817
found to match spectra of authentic compounds and/or spectral data reported
in the literature.
In conclusion, we demonstrated that Barbier–Grignard-type amination
with N,N-dimethyl O-(2,4,6-trimethylphenylsulfonyl)hydroxylamine in THF
at room temperature is a practical method to transfer the Me2Nꢀ moiety
directly to aryl carbanions. Further investigations on the extensions of in
situ protocol for electrophilic amination and the reaction mechanism are
currently in progress in our laboratory.
ACKNOWLEDGMENTS
We thank Ankara University Scientific Research Fund (Grant Nos. 2005-07-
05-096 and 2005-07-05-004 HPD) and the Turkish Scientific and Technical
Research Council (Grant No. 105T292) for their financial support.
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