Scope and utility of CsOH·H2O in animation reactions via direct coupling of aryl halides and sec-alcyclic amines

Article abstract of DOI:10.1055/s-2004-830853

Direct coupling of aryl halides with sec-alicyclic amines promoted by CsOH·H₂O in DMSO to the corresponding aryl substituted amines, with good to excellent yields, is reported herein. A variety of aryl halides and sec-alicyclic amines with a broad range of electronic diversity and functional groups was studied in this transformation, thus offering general applicability in organic synthesis.

Full text of DOI:10.1055/s-2004-830853

LETTER
1747
Scope and Utility of CsOH·H2O in Amination Reactions via Direct Coupling of
Aryl Halides and sec-Alicyclic Amines1
S
cope and Utilityaof CsOH 2
·
H
v
OinAmin
i
ationReactio
V
ns arala, E. Ramu, M. Mujahid Alam, Srinivas R. Adapa*
Inorganic Division, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax +91(40)7160921; E-mail: asrinivas_rao@iict.ap.nic.in
Received 1 December 2003
primary alkyl amines to form corresponding sec-amines
Abstract: Direct coupling of aryl halides with sec-alicyclic amines
promoted by CsOH·H2O in DMSO to the corresponding aryl substi-
tuted amines, with good to excellent yields, is reported herein. A va-
riety of aryl halides and sec-alicyclic amines with a broad range of
in moderate to good yields. Herein, we report our study on
CsOH·H2O-promoted direct cross-coupling reactions of
aryl halides and sec-alicyclic amines to form correspond-
electronic diversity and functional groups was studied in this trans- ing tert-aryl amines. We have chosen a variety of structur-
formation, thus offering general applicability in organic synthesis.
ally divergent aryl halides and sec-alicyclic amines
having a wide range of functional groups in order to better
understand both the scope and the general applicability of
the CsOH·H2O-promoted reaction.
Key words: CsOH·H2O, base, aryl halides, sec-alicyclic amines,
cross coupling
First, we evaluated the feasibility of direct cross-coupling
of 1-bromonaphthalene (1.0 mmol) and morpholine (1.2
mmol) in DMSO using 2 mmol of CsOH·H2O in a sealed
tube (Scheme 1).11 At ambient temperatures, no reaction
between the coupling partners was observed, but heating
the reaction mixture to 120 °C for 5 minutes afforded N-
naphthyl morpholine in 90% yield (entry 1, Table 1).
Amination of aryl halides has been an important and fre-
quently required reaction for the synthesis of the interest-
ing compounds containing N-aryl moiety, which have
wide occurrence in pharmaceuticals,2a agrochemicals,2b
photography,2c xeroxography,2d pigments,2e, and natural
products.2f Elegant work by Hartwig,3 Buchwald4 and
others5 has led to significant improvements in synthetic
amination methodology since its original discovery by
Migita and co-workers in 1983.6 A wide range of transi-
tion metal complexes has been used as catalysts for these
coupling reactions, with attention particularly focused on
palladium and copper based complexes. Although these
methods are quite reliable, practical success has been rel-
atively limited because they usually require long reaction
times or have a relatively narrow substrate application
range.7 Furthermore, use of transition metal complexes
leads to the generation of hazardous waste, which has a
number of environmental health problems associated with
it.8 Lately, Tu and coworkers9 have reported transition
metal-free cross-coupling reactions between primary and
secondary amines and aryl halides using microwave irra-
diation conditions with potassium tert-butoxide as base
and DMSO as a solvent. Thus, development of more im-
proved synthetic methods involving transition-metal free
synthesis of aryl substituted amines still remain an active
research area.
Scheme 1
As a control experiment, the same reaction was carried out
in the absence of CsOH·H2O at 120 °C, when no cross-
coupled product was observed even after heating for a
longer period of time. The optimum yield of the product
is obtained when a ratio of aryl halide to amine of 1:1.2 is
used. Of the solvents tested for this reaction (DMSO–
THF, H2O–TBAB, NMP, and DMSO), DMSO was found
to be the most efficient. In the absence of DMSO, no prod-
uct could be isolated from the crude reaction mixture; thus
solvent plays a vital role in this reaction.
With optimized experimental conditions for morpholine
in hand, we then investigated direct cross-coupling reac-
tions using a variety of electronically divergent sec-alicy-
clic amines and 1-bromonaphthalene. The amines used for
the study include piperidine, 4-methylpiperidine, pyrroli-
dine, and N-substituted piperazines. We have deliberately
chosen N-substituted piperazines for the study to evaluate
both the functional group tolerance and to evaluate gener-
al applicability of CsOH·H2O-promoted direct amination
reaction. The results from this study are shown in Table 1.
All sec-alicyclic amine substrates underwent direct cross-
coupling reactions to afford the corresponding products in
In the last few years, CsOH·H2O-promoted synthetic pro-
tocols have been widely applied to the formation of a va-
riety of carbon-hetero atom and carbon-carbon bond
forming reactions.10 Recently, Jung and co-workers re-
ported an elegant synthetic methodology for direct amina-
tion reactions promoted by CsOH·H2O.10j However, this
report is limited to alkylation of primary alkyl halides and
SYNLETT 2004, No. 10, pp 1747–1750
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Advanced online publication: 28.07.2004
DOI: 10.1055/s-2004-830853; Art ID: D30903ST
© Georg Thieme Verlag Stuttgart · New York

1748
R. Varala et al.
LETTER
Table 1 CsOH·H2O-Promoted Cross-Coupling of 1-Bromonaph-
thalene and Various sec-Aliphatic Amines
under strongly alkaline reaction conditions, piperazines
containing functional groups such as N-Boc and N-acetyl
remained inert, as no hydrolysis to corresponding amines
(entry 9, Table 1) and no side products were observed
(entry 7, Table 1) during the reaction. These results
strongly demonstrate good functional group tolerance for
CsOH·H2O-promoted direct amination of substituted pip-
erazines.
Entry
1
Amine
Time (min)
5
Yield (%)a
90
2
3
10
20
85
58
We have further studied the reaction using a variety of
functionalized aryl halides. The results from this study are
shown in Table 2. Aryl halides having a variety of func-
tional groups undergo smooth reaction providing moder-
ate to excellent yields of the corresponding adducts
(entries 1–18, Table 2). However, aryl halides that contain
p-hydroxy, p-formyl and p-methoxy substituents do not
undergo adduct formation at all under our experimental
conditions (entries 8–10, Table 2). The reaction of 1-bro-
mo-4-nitrobenzene and 1-bromo-4-cyanobenzene with
morpholine and piperidine required no heating at all, as
the reaction took place at room temperature in excellent
yields, respectively (entries 2 and 3, Table 2). Similarly,
their corresponding iodo analogues underwent smooth re-
action with morpholine and piperidine at room tempera-
ture affording excellent yields (entries 12 and 16,
Table 2).
4
5
15
10
66
75
6
15
15
10
62
69
78
Table 2 CsOH·H2O-Promoted Cross-Coupling of Aryl Halides and
Amines
7
Entry
1
Ar-X
Amine
Time
(min) (%)
Yield
10
812
2b
180
210
90
85
9
10
74
3b
240
270
87
82
a Isolated yields.
4
5
6
7
10
10
15
15
60
52
82
55
moderate to good yields, and the reaction times are also
very short (5–20 min) for all examples. In contrast, report-
ed procedures involving transition-metal complexes re-
quire several hours for direct amination reactions.3–5
Among various amines tested, morpholine (entry 1,
Table 1), and piperidine (entry 2, Table 1) gave very good
yields but 4-methyl piperidine and pyrrolidine gave the
corresponding coupled products in only moderate yields
(entry 3 and 4, Table 1). The order of reactivity for these
amines in terms of yield and reaction time can be general-
ized as morpholine>piperidine>pyrrolidine>4-methyl pi-
peridine under our reaction conditions. For N-substituted
piperazines, all substrates gave the corresponding adducts
in good yields (entries 5–8, Table 1). Interestingly, even
8
9
20
20
0
0
Synlett 2004, No. 10, 1747–1750 © Thieme Stuttgart · New York

LETTER
Scope and Utility of CsOH·H2O in Amination Reactions
1749
Table 2 CsOH·H2O-Promoted Cross-Coupling of Aryl Halides and
Amines (continued)
bromobenzene fragments. Likewise, in case of entry 14,
Table 2 the addition product corresponds to a mixture of
the meta/para substitution (1:1). The use of a heterocyclic
aryl bromide (2-bromopyridine) also gave the corre-
sponding adduct in moderate yield (entry 7, Table 2). It is
worthy of note that our studies also demonstrate good
functional group tolerance for CsOH·H2O-promoted ami-
nation reaction for aryl halides containing sensitive func-
tional groups. For example, even under strong alkaline
conditions, aryl halides containing p-cyano groups did not
undergo hydrolysis. Similarly, aryl halides containing the
potentially polymerizable vinyl group (entry 6 and 13,
Table 2) also underwent smooth reaction and gave the
corresponding amines in good isolated yields, no base
induced polymerization being observed.
Entry
10
Ar-X
Amine
Time
(min) (%)
Yield
20
10
0
11
95
12b
150
180
94
87
It has earlier been proposed that direct amination reactions
promoted by strong bases such as potassium tert-butoxide
proceed through a mechanism involving a benzyne inter-
mediate. In fact, direct evidence for a benzyne intermedi-
ate in direct amination reactions has been demonstrated by
experiments involving successful trapping through [2+4]
cycloaddition reactions.9,12 It is highly likely that a similar
benzyne intermediate mediated mechanism is applicable
to CsOH·H2O-promoted reactions as well.
13
14
15
15
10
5
55
62
82
In conclusion, we have shown a rapid and efficient direct
cross coupling of variety of aryl halides and sec-alicyclic
amines having structurally divergent functional groups
and can be carried out using CsOH·H2O. Our studies also
highlight tolerance for sensitive functional groups present
on both the coupling fragments. The wide nature of cou-
pling fragments studied in work offers not only the wide-
scope but also general applicability of CsOH·H2O in rou-
tine synthetic protocols. Efforts to expand the scope of the
method are currently underway in our laboratory.
16b
180
210
90
85
17
18
10
15
72
75
Acknowledgment
a Isolated yields.
V. R and M. M. Alam are thankful to Dr. B. M. Choudary for
constant encouragement and Dr. H. Maheswaran for discussions.
V. R. and M. M. Alam also thank Council of Scientific Industrial
Research for financial support.
b Room temperature.
Reaction times for the iodo analogues are shorter than
those required for the corresponding bromo analogues.
Chlorobenzene and fluorobenzene did not react at all un-
der our experimental conditions. However, when 4-nitro-
chlorobenzene and 2-cyanofluorobenzene were subjected
to reaction with morpholine (entries 17 and 18, Table 2),
we obtained the corresponding adducts in good yields in
about 10–15 minutes. These results clearly demonstrate
that highly electron-withdrawing substituents on the aryl
moiety of the coupling fragment strongly facilitate cou-
pling. Furthermore, it can be generalized that electron rich
aryl halides gave poor yields or no product under our ex-
perimental conditions with the exception that p-amino-
bromobenzene upon coupling with morpholine gave the
corresponding meta-amination product in poor yield
(entry 5, Table 2). We have not observed products that are
derived from direct coupling between two p-amino-
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Synlett 2004, No. 10, 1747–1750 © Thieme Stuttgart · New York