Copper-catalyzed ortho-C-H amination of protected anilines with secondary amines

Article abstract of DOI:10.1039/c3cc49633c

A practical Cu-catalyzed picolinamide-directed o-amination of anilines showing excellent mono-substitution selectivity and high functional group tolerance has been developed.

Full text of DOI:10.1039/c3cc49633c

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Copper-catalyzed ortho-C–H amination of
protected anilines with secondary amines†
Cite this:DOI: 10.1039/c3cc49633c
´
Angel Manu Martınez, Nuria Rodrıguez,* Ramon Gomez Arrayas* and
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´
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´
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Received 19th December 2013,
Accepted 22nd January 2014
Juan C. Carretero
DOI: 10.1039/c3cc49633c
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A practical Cu-catalyzed picolinamide-directed o-amination of secondary amines using a readily removable 2-picolinic acid
anilines showing excellent mono-substitution selectivity and high directing group.4g–j,12
functional group tolerance has been developed.
Based on our earlier results,13,14 we initially envisioned that the
N-(SO2Py) protecting group could assist the Cu-catalyzed inter-
The ubiquity of arylamines1 among pharmaceuticals, natural molecular o-C–H amination of anilines. Nonetheless, we observed
products and materials continues to inspire the development of much higher reactivity when using the closely related N-COPy
efficient and sustainable methods for the construction of aryl directing group.15 The model reaction of picolinamide 1 with
C–N bonds. The direct cross-dehydrogenative coupling between morpholine gave traces of the o-amination product 2 under
arenes and R2NH represents an appealing approach2 that conditions similar to those reported by Daugulis:12 Cu(OAc)2–
complements standard procedures for N-aryl bond formation relying Ag2CO3 (25 mol%) and NMO (2.0 equiv.) as an oxidant in NMP or
on pre-activated substrates such as the Ullmann–Goldberg, DMSO at 130 1C for 16 hours (Table 1, entry 1). Just switching the
Buchwald–Hartwig and Chan–Lam aminations.3 In this context, oxidant to O2 led to an encouraging yield of 27% (entry 2). At this
the Pd-catalyzed intermolecular amination of arenes with R2NH point, some control experiments showed that Cu(OAc)2 was
is emerging as an increasingly viable tool.4,5
essential (entry 3), whereas Ag2CO3 could be absent (entry 4).
Cu-catalyzed C–H amination represents a distinct challenge A brief screening of solvents (entries 5–7) revealed that the use of
that has stimulated substantial research effort since the pioneering
reaction of 2-phenylpyridine with tosylamide reported by Yu et al.
in 2006.6 However, most of the reports have focused on
Table 1 Evaluation of the reaction conditions
intramolecular processes7 or base-promoted reactions at acidic
C–H bonds.8,9 In contrast, Cu-catalyzed intermolecular amination of
‘‘inert’’ aryl C–H bonds has been mainly limited to arenes with the
non-removable 2-pyridyl directing group.10,11 Daugulis’s group has
recently overcome this limitation and developed a removable
Yielda [%]
directing group strategy for the Cu-catalyzed amination of
non-acidic benzamide derivatives assisted by 8-aminoquinoline
and 2-picolinic acid auxiliaries.12 Despite this progress, the
Cu-catalyzed intermolecular amination of arenes is in its infancy
in terms of scope and practicality.
Recently, we have introduced the 2-pyridylsulfonyl group
(SO2Py) as an effective N-protecting/directing group for the
Cu-catalyzed o-C–H halogenation of anilines.13 Herein we disclose
the Cu-catalyzed o-C–H amination of aniline derivatives with
Oxidant
Additive
Solvent
T [1C]
1
NMO
Ag2CO3
Ag2CO3
Ag2CO3
—
—
—
—
—
—
—
NMP
NMP
NMP
NMP
DMSO
DMPU
p-Xylene
p-Xylene
p-Xylene
p-Xylene
p-Xylene
130
130
130
130
130
130
130
130
130
130
60
Traces
27
—
23
21
2
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
3b
4
5
6
30
7
48c
8d
9
62 (60)e
85 (84)e
85 (83)e
75 (74)e
10 f
11f
—
´
´
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Departamento de Quımica Organica, Universidad Autonoma de Madrid,
Cantoblanco, 28049 Madrid, Spain. E-mail: n.rodriguez@uam.es,
ramon.gomez@uam.es
Conditions: aniline 1 (0.20 mmol), morpholine (0.40 mmol), Cu(OAc)2
(25 mol%), oxidant (2.0 equiv.), additive (25 mol%), solvent (0.2 M), 16 h
b
and N2.a GC yields (n-C16H34 as internal standard). In the absence of
c
d
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data of new compounds and copies of NMR spectra. See
DOI: 10.1039/c3cc49633c
Cu(OAc)2. 60% GC yield after 48 h. Reaction under microwave:
e
f
130 1C/150 W/3 h. Isolated yield. Cu(OAc)2 (15 mol%) and
PhI(OAc)2 (1.20 equiv.).
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Table 2 Evaluation of the N-directing/protecting group
Entry
PG/R (Substrate)
Product
Yielda [%]
71 (74)b
1
2
3
4
5
6
7
C(O)(2-Py)/H (1)
C(O)(Ph)/H (3)
Ac/H (4)
SO2(2-Py)/Me (5)
H/H (7)
Ts/H (6)
C(O)(2-Py)/Me (8)
2
—
c
—
—
c
—
9 + 10d (1 : 1)
30
e
—
—
—
—
c
—
c
—
a
b
c
GC yields (n-C16H34 as internal standard). Isolated yield. Starting
aniline recovered. d 10 = N,N-diphenylpyridine-2-sulfonamide. Complex
e
mixture.
p-xylene, a non-polar solvent, could increase the yield up to 48%
(entry 7, 60% upon prolonging the reaction time to 48 hours).
The decisive factor in making the transformation effective
was the choice of PhI(OAc)2 as the oxidant (see the ESI† for
further studies).16 Full conversion in 16 hours was observed
with 2 equivalents of PhI(OAc)2, allowing the desired product 2
to be isolated in 84% yield (entry 9). The loading of both the Cu
catalyst (15 mol%) and PhI(OAc)2 (1.2 equiv.) could be signifi-
cantly reduced without an appreciable impact (83%, entry 10).
Moreover, the temperature could be lowered to 60 1C while
maintaining a synthetically useful yield (74%, entry 11). It is
remarkable that no diamination products were detected in the
crude mixtures.
Scheme 1 Cu-catalyzed o-amination of aniline substrates with morpholine.
Isolated yields for products 29–47. Cu(OAc)2 (25 mol%) and PhI(OAc)2
(2.0 equiv.).
a
b
of the two mono-o-aminated products (40 and 41). o-Substitution
A screening of protecting groups confirmed the superiority led to reduced reactivity (45, 27% yield), presumably because of
of the COPy group, emphasizing the cooperative directing its increased steric requirements, while the 1-naphthyl derivative
role of both CO and 2-Py moieties (Table 2). The lack of reactivity was aminated at C2 (46, 50% yield). A heteroaromatic amine was
of benzanilide 3 and acetanilide 4 revealed the importance also amenable to the reaction, albeit in lower yield (47, 35%).
of the 2-Py unit (entries 2 and 3). However, the coordinating
Several morpholine, piperidine and piperazine derivatives
NH-(SO2Py) substrate 5 afforded, with low conversion, the bearing common functionalities including ethers, esters and
desired o-aminated product 9 accompanied by the N-arylated pro- nitriles performed well in this reaction (Scheme 2). Unfortunately,
duct 10 (1 : 1 mixture), the latter arising from the reaction of 5 with simple secondary amines proved to be much less effective
the iodobenzene generated as a byproduct (entry 4). The reaction of (products 56 and 57).
the free aniline or its N-tosyl derivative was totally unproductive
(entries 5 and 6). Finally, N-alkylation was not tolerated, the up to 1 gram-scale without loss of yield (see the ESI† for details)
N(Me)(COPy)-aniline 8 being recovered unaltered (entry 7). and the efficient directing group removal under basic conditions
Finally, we demonstrated both the scale-up of the reaction
The reaction of variously substituted aniline derivatives with (Scheme 3, product 58, 96% yield). The resulting 2-morpho-
morpholine is presented in Scheme 1. Substrates with electron-rich linoaniline was next derivatized into the corresponding benz-
(Me and OMe) and moderately electron-deficient (F, Cl and Br) imidazol 59 via an oxidative cyclization reaction.17 Although the
substituents at the p-position reacted particularly well (typically mechanism is unclear at this point, the lack of reactivity of 1 in
60–81% yield). Even the strongly coordinating NMe2 (29, 43%) the presence of radical scavengers such as TEMPO or Galvinoxyl
and the unprotected hydroxymethyl (32, 46%) groups were suggests that a SET pathway might operate18 (see the ESI† for
tolerated. The complete o-selectivity was particularly noteworthy intramolecular kinetic isotope effect and competition studies).
in the p-(OMe)- and p-(NMe2)-aniline derivatives, with two
In summary, we have developed a regioselective Cu-catalyzed
o-directing groups. Strongly electron-withdrawing groups, such ortho-C–H amination process assisted by a removable N-COPy
as CO2Me, CF3, CN or the base-sensitive COMe group, were group that provides a straightforward means for the preparation
compatible but resulted generally in lower yields and required of o-aminoaniline derivatives.
higher loadings of Cu (25 mol%) and PhI(OAc)2 (2 equiv.).
We thank the Spanish Government (MINECO, CTQ2012-35790)
m-Substituted substrates reacted generally with complete regio- and the Madrid regional government (AVANCAT, S2009/PPQ-1634)
control at the sterically less hindered site (42 and 43). As an for financial support. N.R. thanks the MICINN for a Ramon y Cajal
exception, the aniline with a m-OMe group led to a 2 : 1 mixture contract and the Marie Curie Foundation (CIG: CHAAS-304085).
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Scheme 3 Deprotection of 2 and synthesis of the benzimidazole 59.
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