Direct base-assisted C-N bond formation between aryl halides and aliphatic tertiary amines under transition-metal-free conditions

Article abstract of DOI:10.1002/ejoc.201101618

Direct base-mediated amination of aryl halides with aliphatic tertiary amines via an aryne intermediate was developed under transition-metal-free conditions. This operationally simple C-N bond-coupling protocol could tolerate a variety of functionalized aryl halides as well as several aliphatic tertiary amines. Moreover, this environmentally benign process provides a new strategy for direct C-N bond formation.

Full text of DOI:10.1002/ejoc.201101618

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101618
Direct Base-Assisted C–N Bond Formation between Aryl Halides and Aliphatic
Tertiary Amines under Transition-Metal-Free Conditions
Yang Fang,[a][‡] Yueqin Zheng,[a][‡] and Zhiyong Wang*[a]
Keywords: Amination / Cross-coupling / Arynes
Direct base-mediated amination of aryl halides with aliphatic
tertiary amines via an aryne intermediate was developed un-
der transition-metal-free conditions. This operationally sim-
ple C–N bond-coupling protocol could tolerate a variety of
functionalized aryl halides as well as several aliphatic terti-
ary amines. Moreover, this environmentally benign process
provides a new strategy for direct C–N bond formation.
of arynes with tertiary amines would lead to efficient C–N
bond formation, because the nitrogen bears a partial nega-
tive charge to exhibit considerable nucleophilicity.
Introduction
Amination of aryl halides has emerged as a valuable syn-
thetic tool for the construction of aromatic amines.[1] The
resulting N-aryl moieties are privileged building blocks that
have wide applications in the fields of electronic materials[2]
and pharmaceuticals.[3] Typically, C–N bonds are formed
by copper-mediated Ullmann[4] and Goldberg[5] type reac-
tions or by Buchwald–Hartwig type aminations[6] utilizing
palladium or nickel catalysts with the aid of amine or phos-
phane ligands. Recently, Beller[7] and Williams[8] indepen-
dently discovered alkylation between amines to generate
aromatic amines under Ru or Ir catalysis. In the pursuit of
more environmentally benign reaction process, Tu,[9]
Bolm,[10] and other groups[11] have developed the arylation
of primary and secondary amines under transition-metal-
free conditions. These green chemical transformations avoid
bringing metallic impurities into the products, simplifying
purification for pharmaceutical applications. However, to
the best of our knowledge, the direct amination of aryl hal-
ides with tertiary amines has not been reported. Our group
decided to examine an aryne-based methodology for the
construction of the N-aryl moiety by employing tertiary
amines as a suitable nitrogen source.
Results and Discussion
Based on previous studies, strongly basic conditions are
essential to furnish arynes in situ from aryl halides.[9,12a,13]
Accordingly, we began our investigation with the model re-
action of bromobenzene with N-ethylpiperidine in the pres-
ence of strong bases at 130 °C. The optimized results are
summarized in Table 1. Initially, a library of strong bases
was examined by using DMSO as solvent (Table 1, En-
tries 1–5). Of the bases screened, KOH gave the best result
for this direct amination (Table 1, Entry 2). Weaker bases
were less effective for this direct transformation (Table 1,
Entries 1, 3, and 4).
When the stronger base tBuOK was used instead of
KOH, a decreased yield was obtained due to the partial
formation of tBuOPh (Table 1, Entry 5). Next, the solvent
effect was examined and DMSO was found to be consider-
ably superior to other aprotic solvents such as DMF, NMP,
m-xylene, and dioxane (Table 1, Entries 6–9). Besides, when
the amount of KOH was decreased to 2 equiv., a slightly
decreased yield was observed (Table 1, Entry 10). Screening
of other typical reaction parameters (reaction time, tem-
perature) revealed that the best result could be obtained
when the reaction was performed in KOH/DMSO at 130 °C
for 24 h (see Supporting Information for details). This opti-
mized result clearly indicated that the mixture of KOH/
DMSO (pKa = 30–32) can serve as a superbase[14] to accel-
erate this direct amination efficiently.
Aryne methodologies have recently proven valuable for
the facile construction of benzo-fused heterocycles and sub-
stituted arenes.[12] Considering the reactive character arising
from CϵC bonds, a suitable combination of arynes with
nitrogen, oxygen, or sulfur nucleophiles could lead to many
synthetic applications. We assumed that nucleophilic attack
[a] Hefei National Laboratory for Physical Sciences at Microscale,
CAS Key Laboratory of Soft Matter Chemistry and
Department of Chemistry, University of Science and
Technology of China, Hefei,
With the best reaction conditions in hand, the coupling
of bromobenzene with acyclic and cyclic tertiary amines
was investigated (Table 2). It was found that bulky acyclic
tertiary amines were suitable nucleophiles to deliver the aro-
matic amines efficiently under the optimized conditions
Anhui 230026, P. R. China
Fax: +86-551-3603185
E-mail: zwang3@ustc.edu.cn
[‡] These authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101618.
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Y. Fang, Y. Zheng, Z. Wang
SHORT COMMUNICATION
Table 1. Effects of base and solvent on the coupling reaction.[a]
After investigating the generality of tertiary amines in the
reaction, the scope of the aryl halides was also explored
(Table 3, Entries 1–9). As expected, a more reactive aryl
iodide and a less reactive aryl chloride are also effective in
these transformations (Table 3, Entries 1 and 2). Addition-
ally, the steric and electronic effects on the C–N cross-cou-
pling reaction were investigated (Table 3, Entries 3–9). Ex-
perimental results indicated that the steric effect was signifi-
cant to the reaction yields and selectivities. The reactions of
para- and meta-substituted bromobenzene afforded higher
yields (Table 3, Entries 4 and 5), whereas the more sterically
hindered ortho-substituted bromobenzene was less reactive
(Table 3, Entry 3). On the other hand, the ortho-substituted
bromobenzene showed higher selectivity than para- and
meta-substituted bromobenzene (Table 3, Entry 3). Elec-
tronic effects do not have a substantial influence on the re-
action. Substrates bearing different groups underwent di-
rect amination smoothly to afford the corresponding
amines with moderate yields regardless of whether a strong
electron-donating methoxy group or an electron-with-
drawing trifluoromethyl group was substituted onto the aryl
halides moiety (Table 3, Entries 6 and 7).
[a] Reaction conditions: bromobenzene (0.5 mmol), N-ethylpiper-
idine (1.5 mmol), base (1.5 mmol), dry solvent (0.5 mL) at 130 °C,
24 h. [b] Isolated yield.
(Table 2, Entries 1–4). Even when triisoamylamine was em-
ployed as a nitrogen source, the corresponding arylamine
was obtained with a satisfactory yield of 61% regardless of
the bulky steric hindrance (Table 2, Entry 4). For cyclic N-
ethylpiperidine, the reaction also proceeded smoothly to
give desired amine 1e in 71% yield (Table 2, Entry 5). Inter-
estingly, when cyclic N-methylpiperidine was employed as a
nucleophile, formation of the desired product was not ob-
served, but terminal alkene 1f was obtained instead
(Table 2, Entry 6).
Table 3. Direct amination of aryl halides and N-ethylpiperidine.[a]
Table 2. Direct amination of bromobenzene and tertiary amines.[a]
[a] Reaction conditions: bromobenzene (0.5 mmol), N-ethylpiper-
idine (1.5 mmol), KOH (1.5 mmol), dry DMSO (0.5 mL) at 130 °C,
24 h. [b] Isolated yield.
[a] Reaction conditions: aryl halide (0.5 mmol), N-ethylpiperidine
(1.5 mmol), KOH (1.5 mmol), dry DMSO (0.5 mL) at 130 °C, 24 h.
[b] Isolated yield.
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Direct Base-Assisted C–N Bond Formation under Metal-Free Conditions
Scheme 1. A possible mechanism accounting for the formation of 1e and 1f.
dried with anhydrous Na2SO4, and the solvents were evaporated in
On the basis of the experimental results and the known
chemistry of arynes,[9,15] a possible mechanism accounting
for the reaction process was proposed (Scheme 1). First, the
benzyne intermediate was generated in situ in the superbase
media (KOH/DMSO). When N-ethylpiperidine is employed
as the nucleophile, the partially negative nitrogen attacks
the reactive intermediate benzyne to generate zwitterion I.
Subsequent Hofmann-type elimination and protonation
leads to final product 1e. Similarly, when N-methylpiper-
idine is employed as the nitrogen source, zwitterion II can
be generated efficiently, which can then undergo Hofmann-
type elimination and protonation to produce terminal alk-
ene 1f. According to the proposed aryne intermediate, the
regioselectivity of the direct amination could be explained.
For example, when ortho-substituted bromobenzene was
employed as the benzyne precursor, the amination preferen-
tially performs at the meta position due to both electronic
and steric effects, as shown in Table 3 (Entry 3), which is in
accordance with the chemistry of arynes.[16]
vacuo to give the crude product. Purification of the residue by flash
column chromatography afforded the desired aromatic amines
(Note: column chromatography should be performed quickly).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details for the direct amination are presented.
1H and 13C NMR spectra are also given for all the products.
Acknowledgments
The authors are grateful to the National Nature Science Founda-
tion of China (20932002, 20972144, 90813008, 20772188, and
J1030412).
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Experimental Section
General Procedure for the Direct Aminations: To a mixture of the
tertiary amine (1.5 mmol) and KOH (1.5 mmol) in dry DMSO
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Received: November 9, 2011
Published Online: February 8, 2012
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