Catalytic C-H Amination with aromatic amines

Article abstract of DOI:10.1002/anie.201201921

Aniline joins the club: A β-diketiminato copper(I) catalyst enables C-H amination of anilines employing low catalyst loadings to preclude oxidation to the diazene ArNi-NAr (see scheme). Electron-poor anilines are particularly resistant towards diazene formation and participate in the amination of strong and unactivated C-H bonds. N-alkyl anilines also take part in C-H amination. Copyright

Full text of DOI:10.1002/anie.201201921

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DOI: 10.1002/anie.201201921
À
C H Functionalization
À
Catalytic C H Amination with Aromatic Amines**
Raymond T. Gephart III, Daria L. Huang, Mae Joanne B. Aguila, Graham Schmidt,
Andi Shahu, and Timothy H. Warren*
The prevalence of basic nitrogen atoms in myriads of small
molecules of biological interest motivates the development of
methodologies to streamline the introduction of nitrogen
À
atoms into organic molecules. C H amination offers a poten-
tially highly atom-economical approach, directly converting
[1]
C H into C N bonds. Prototypical nitrene-based routes[2]
À
À
À
for Csp3 H amination typically employ the iminoiodinanes
PhI N(EWG) (EWG = SO2R’ or C(O)OR’) as nitrene trans-
=
À
fer reagents with a range of catalysts to aminate C H bonds in
the substrates R-H to provide the corresponding secondary
amines RNH(EWG). Though rhodium-[1e,3] and ruthenium-
based[4] catalysts are perhaps most common, a growing
number of catalyst systems employing Earth abundant first-
row transition metals such as Mn,[5] Fe,[6,7] Co,[8] and Cu,[9]
have been developed.
1
2
À
C H amination with secondary amines HNR R requires
non-nitrene-based routes. Liu and co-workers[10] and White
and co-workers[11] independently described allylic C H
À
amination with sulfonyl carbamates MeOC(O)NHSO2R in
which cationic Pd–allyl complexes serve as key intermediates.
Mildly basic diarylamines such as HNAr2 also participate in
1
2
À
Scheme 1. C H amination with alkyl amines HNR R catalyzed by
[(Cl2NN)Cu] with proposed catalytic cycle.
[12a]
À
allylic C H amination,
and N-fluorobis(phenylsulfonyl)-
À
imide (NFSI) may be used for palladium-catalyzed C H
amidation of substrates which possess directing donor
groups.[12b] A 1,10-phenanthroline-based copper(I) catalyst
employs MeNHSO2Ph with tBuOOR (R = O2CMe, O2CAr)
as an oxidant to give tertiary sulfonylamines derived from
allylic and benzylic substrates.[13,14] The near ubiquitous
requirement of very strong electron-withdrawing groups on
the nitrogen atom, however, severely limits the range of N-
based functionalities that may be directly incorporated
the secondary amines morpholine and piperidine may also be
used. Through its isolation and reactivity studies, the cop-
per(II) amide [(Cl2NN)Cu-NHAd] serves as a key intermedi-
ate that participates in both hydrogen atom abstraction
(HAA) of the substrates R-H and capture of the resulting
[9b]
À
radical RC to give the C H amination product R-NHAd.
À
Aiming to extend our C H amination protocol to
aromatic amines H2NAr, we were quite concerned that our
system would instead catalyze their oxidation to diazenes
À
through C H amination, though in some cases simple organic
[15]
amides[9d] or imidazoles[7b] may be employed.
ArN NAr. Although first reported in 1955,
the use of
=
We recently showed that the b-diketiminato copper(I)
complex [{(Cl2NN)Cu}2(m-benzene)] (1) catalyzes the amina-
copper(I) halides in pyridine for the aerobic oxidation of
anilines into azobenzenes recently has been rediscovered as
a versatile method for the synthesis of aromatic diazenes.[16]
À
tion of Csp3 H bonds of ethylbenzene, indane, and even the
completely unactivated substrate cyclohexane with the pri-
mary alkylamines 1-adamantylamine, cyclohexylamine, and
phenethylamine employing tBuOOtBu as an oxidant (Sche-
me 1).[9b] Emphasizing the non-nitrene nature of this protocol,
Indeed, early mechanistic studies suggested copper(II) ani-
II
À
lides Cu NHAr as key intermediates which are subject to
À
bimolecular N–N coupling to give the hydrazines ArNH
[15b,c]
=
NHAr en route to diazenes ArN NAr (Scheme 2).
We began with scouting experiments employing 2,4,6-
trimethylaniline (H2NMes) with neat ethylbenzene as a sub-
strate and tBuOOtBu as an oxidant, catalyzed by 10 mol%
[Cu] at 908C. Despite the high conversion of the aniline
(> 95%), the desired secondary amine PhCH(NHMes)Me is
produced in only 21% yield accompanied by a significant
[*] R. T. Gephart III, D. L. Huang, M. J. B. Aguila, G. Schmidt, A. Shahu,
Prof. T. H. Warren
Department of Chemistry, Georgetown University
Box 571227, Washington, DC 20057-1227 (USA)
E-mail: thw@georgetown.edu
=
amount of the diazene MesN NMes. We find that decreasing
[**] We acknowledge funding from the National Science Foundation
(CHE-1012523) to T.H.W.
the concentration of [(Cl2NN)Cu] either by lowering the
loading of this catalyst (to 1 mol%) or increasing the solvent
volume (to 20 mL) led to marked increases in the amount of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201921.
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[a]
À
Table 1: C H amination of hydrocarbons with H2NMes.
[b]
À
R H
À
Entry
C H BDE
Yield [%]
[kcalmolÀ1
]
Scheme 2. Oxidation of anilines and hydrazines by [Cu]/tBuOOtBu
catalyst system gives diazenes.
1
2
3
83
95
85
60
85
87
À
the C H amination product with a concomitant reduction in
=
the diazene MesN NMes (Figure 1; see Table S1 and Fig-
ures S1 and S2 in the Supporting Information).
4
5
90
97
18
40
[a] Reaction conditions: 1 mmol H2NMes, 1.2 mmol tBuOOtBu, 20 mL
1
À
neat substrate, 1 mol% [Cu], 908C, 24 h; H NMR yields. [b] C H BDEs
from Ref. [17].
Figure 1. Dependence of product yield on catalyst concentration in the
À
C H amination of ethylbenzene by H2NMes.
Based on the dramatic effect that the catalyst concen-
tration has on diazene formation, we hypothesize that
a bimolecular reaction occurs between two copper(II) anilido
intermediates, [CuII]-NHMes (formed by reaction of [CuII]-
À
OtBu with H2NMes; see Scheme 1), to give MesNH NHMes
=
which may be subsequently oxidized to MesN NMes
À
(Scheme 2). Consistent with this hypothesis, PhNH NHPh
=
is oxidized to PhN NPh under catalytic conditions (100%
conversion, 85% diazene yield; Scheme 2). The reaction of
H2NPh or H2NMes with tBuOOtBu in the presence of the
À
Figure 2. C H amination product yields with a series of p-substituted
anilines H2NAr in neat ethylbenzene.
À
catalyst [Cu] but in the absence of a Csp3 H substrate leads to
complete consumption of the primary aromatic amine, thus
=
=
forming PhN NPh and MesN NMes in 57 and 72% yield,
respectively.
2
À
parameter (R = 0.99) as well as the N H bond strength for
We then examined the dependence of the substrate C H
bond strength on the selectivity for C H amination versus
diazene formation when employing H2NMes and tBuOOtBu
with 1 mol% [Cu] at 908C (Table 1). The neat substrates
cyclohexane (40% yield), toluene (18%), ethylbenzene
(60%), indane (85%), and 1,2,3,4-tetrahydronaphthalene
the parent aniline (R2 = 0.93; see Figure S4 in the Supporting
Information). Anilines possessing electron-withdrawing sub-
stituents are particularly resistant toward diazene formation.
For instance, attempted oxidation of 2,4,6-Cl3C6H2NH2 with
tBuOOtBu in benzene with 1 mol% [Cu] gives less than 5%
of the corresponding diazene after 24 hours at 908C.
À
À
À
(95%) give C H amination product yields that generally
The reluctance of 2,4,6-Cl3C6H2NH2 to undergo oxidation
to the corresponding diazene under our catalytic conditions
identifies it as an excellent amine for the functionalization of
À
increase with decreasing C H bond strength.
A key insight into diazene formation is revealed by
À
À
monitoring the selectivity for C H amination with a series of
p-substituted anilines p-XC6H4NH2 in neat ethylbenzene
challenging C H substrates. In neat ethylbenzene and
À
cyclohexane, C H amination with 2,4,6-Cl3C6H2NH2 gives
(Figure 2). Electron-withdrawing groups greatly enhance
selectivity for C H amination over diazene formation: the
the corresponding N-alkyl-substituted anilines in 99 and 97%
yield, respectively (Scheme 3). Thus, anilines possessing
electron-withdrawing groups are especially effective in the
À
particularly electron-poor p-cyano derivative gives a yield of
95%. This trend follows both the Hammett-Brown s+
functionalization of completely unactivated Csp3 H bonds.
À
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pentane, readily loses H2NMes in [D6]benzene, thus indicat-
ing that aniline substrates and products do not likely inhibit
À
catalytic C H amination (Scheme 4; Figures S10 and S12).
A subtle change in the catalytic reaction conditions allows
À
the isolation of cyclohexene C H amination products in up to
97% yield (Table 2). The use of 10 equivalents of cyclo-
hexene, 1 equivalent of the aniline 4, and 1.2 equivalents of
[a]
À
Table 2: C H amination of cyclohexene with aniline derivatives.
Scheme 3. C H amination of hydrocarbons with H2NArCl3. Yields
À
1
determined by H NMR spectroscopy. [a] Isolated in 95% yield.
These observations reveal a combination of factors
À
required to achieve high C H amination yields with modest
À
C H substrate loadings: a) low catalyst concentrations to
À
prevent bimolecular N N coupling, b) anilines with electron-
poor substituents, and c) substrates with somewhat lower
À
C H bond strengths.
We examined a broader range of anilines with cyclo-
À
À
hexene which possesses a C H bond of modest strength (C H
BDE ꢀ 82 kcalmolÀ1).[17] We were initially surprised at the
À
low conversions of anilines (1 mmol scale) in C H amination
when performed in neat cyclohexene ca. 20 mL). Since
alkenes may bind to copper(I) complexes,[18] we considered
inhibition by coordination of cyclohexene to the [(Cl2NN)Cu]
catalyst. Indeed, the cyclohexene adduct [(Cl2NN)Cu(h2-
cyclohexene)] (2) readily forms upon addition of cyclohexene
to 1 in [D6]benzene (Scheme 4; see Figures S9 and S11 in the
Supporting Information). Thus, cyclohexene binds more
strongly to the [CuI] center than benzene and may adversely
affect catalyst performance by impeding the oxidation of
[CuI] by tBuOOtBu (Scheme 1). In contrast, [(Cl2NN)Cu-
(NH2Mes)] (3), isolated by addition of H2NMes to 1 in
[a] Reaction conditions: 1 mmol aniline, 1.2 mmol tBuOOtBu, 10 mmol
cyclohexene, 1 mol% [Cu], 908C. Aniline structures are shown and the
yields are those of the isolated products. [b] Used 5 mol% [Cu] and yield
was determined by 1H NMR spectroscopy.
tBuOOtBu with 1 mol% [Cu] catalyst under essentially
À
solventless conditions enables C H amination with a wide
range of anilines. Both electron-rich and electron-poor ani-
À
lines participate in C H amination, though the presence of
electron-withdrawing groups typically enhances the product
yield.
When considering anilines with electron-releasing methyl
substituents, those that provide modest steric hindrance to the
N atom (4b and 4d) result in higher yields. Anilines with
larger o-alkyl substituents (4e–g), however, gave lower yields
because of limited conversion of the aniline substrates,
À
perhaps reflecting a sluggishness in the formation or C H
Scheme 4. X-ray structures of 2 and 3 illustrate coordination of cyclo-
hexene and H2NMes to the [(Cl2NN)Cu] catalyst.[23] The thermal
ellipsoids are shown at 50% probability. See full crystallographic
details in the Supporting Information.
amination reactivity of the putative [CuII]-NHAr intermedi-
ates. Increasing the catalyst loading to 5 mol% modestly
increased the amination yields to 41, 40, and 32% (1H NMR)
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conversion of aniline substantially increased, but so too did
the formation of the corresponding diazene. Little diazene
was observed for the o-tBu-substituted aniline (4g); con-
version of this sterically demanding aniline was a concern at
both low (1 mol%) and high (5 mol%) catalyst loadings.
Anilines possessing electron-withdrawing groups provide
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À
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amination of cyclohexane with morpholine using this catalyst
system.[9b]
In conclusion, we present the first general use of anilines
À
À
in the C H amination of a range of substrates with Csp3
bonds. Previous related, though isolated, examples involve
H
À
polyfluorinated arenes possessing acidic Csp2 H bonds with
electron-poor anilines[21] or sterically hindered bromoarenes
À
which undergo C H functionalization of an o-tBu group
under attempted Buchwald–Hartwig cross-coupling with ani-
lines.[22]
The copper(I) catalyst [{(Cl2NN)Cu}2(benzene)] in con-
junction with the mild oxidant tBuOOtBu enables the direct
À
use of a variety of commercially available anilines in C H
À
amination. Even strong, unactivated Csp3 H bonds may be
efficiently functionalized by using low catalyst loadings and
electron-poor anilines which suppress diazene formation. We
rationalize these findings to result from the competition
between the involvement of putative [CuII]-NHAr intermedi-
À
ates in C H functionalization vs. their undesired bimolecular
coupling which appears to be disfavored for electron-poor
anilines. Future studies target the isolation of discrete
copper(II) anilides [(Cl2NN)Cu-NHAr] and an examination
of their reactivity patterns to lay a concrete mechanistic
À
foundation for this unique C H amination system that
tolerates both alkyl and arylamines.
Received: March 10, 2012
Published online: May 15, 2012
À
Keywords: amination · anilines · C H functionalization ·
copper · synthetic methods
.
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