Copper-catalyzed C2-H amidation of unactivated arenes by N-tosyloxycarbamates

Article abstract of DOI:10.1039/c3cc46412a

(Neocuproine)Cu PF₆ catalyzes the C-H amidation of unactivated arenes by N-tosyloxytrichloroethylcarbamates. Alkyl benzenes are selectively converted to aromatic amines and substituted arenes display variable regioselectivity. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc46412a

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Copper-catalyzed Csp
2
–H amidation of unactivated
arenes by N-tosyloxycarbamates†
Cite this: Chem. Commun., 2013,
49, 10965
Alex John, Jeena Byun and Kenneth M. Nicholas*
Received 21st August 2013,
Accepted 10th October 2013
DOI: 10.1039/c3cc46412a
www.rsc.org/chemcomm
[(Neocuproine)Cu]PF6 catalyzes the C–H amidation of unactivated as oxycarbamates, obviating the need for an external oxidant.17–20
arenes by N-tosyloxytrichloroethylcarbamates. Alkyl benzenes are Herein we disclose a novel C–H amination of simple unactivated
selectively converted to aromatic amines and substituted arenes arenes employing synthetically versatile and conveniently deprotect-
display variable regioselectivity.
able Troc-carbamate21 as the N-reagent under Cu-catalysis.
We began by testing several catalyst/N-reagent combinations
Transition metal catalyzed C–H functionalization has revolutionized using benzene as the test substrate. Initial attempts with
the chemist’s approach to organic synthesis.1,2 The ubiquitous benzophenone O-acetyloxime16a and N-benzoylpiperidine19b as
presence of aromatic amines among natural products, phar- N-reagents and Cu(I)TC (TC = thiophene-2-carboxylate) did not
maceuticals, specialty chemicals and synthetic intermediates,3,4 yield any product. Based on the reactivity of oxycarbamates in
has recently stimulated efforts to develop efficient arene C–H Pd- and Rh-catalyzed directed arene C–H aminations,20,21c we
amination reactions.5,6 This methodology typically has relied on shifted our focus to the use of N-tosyloxycarbamates. Gratifyingly,
pre-installed metal-coordinating directing groups7 to effect the when N-tosyloxy-trichloroethylcarbamate was used as the N-reagent
reaction, which need to be removed post functionalization.
with 20 mol% Cu(I)TC in benzene as solvent at 140 1C, the
Reports of direct C–H N-functionalization of arenes lacking N-phenylcarbamate 1 was detected in 15% yield, along with
activating/directing groups, however, are sparse and limited in trichloroethanol and O-tosyltrichloroethanolate, derived from
substrate and N-reagent scope.8 The direct conversion of benzene decomposition of the carbamate, as well as trace amounts of
to aniline using redox active transition metal oxides with NH3/O2 or aminated toluenes (eqn (1)).‡
hydroxylamine as N-reagents proceeds with moderate efficiency,
but its substrate scope is unknown.9 Transition metal-promoted
10
arene amination by PhIQNTs has been catalyzed by: (1) AuCl3
and (2) TpBr Cu(MeCN), but alkylaromatics undergo benzylic
11
3
+
amination with both systems; (3) Cu(2,9-diaryl-phenanthroline)2 ,
(1)
which promotes amination of electron-rich arenes, but is ineffective
for benzene;12 and (4) a scorpionate Fe(II) complex,13 which shows
rare selectivity for aromatic over benzylic amination. Very recently,
Various copper sources were then screened for catalytic
a regio- (meta- and para-) and chemo-selective C–H amination of activity. The best yield of 1 (ca. 45%, Table 1, entry 5) was
arenes by phthalimide–PhI(OAc)2/Pd(OAc)2–P(t-Bu)3 was reported.14 obtained with [Cu(CH3CN)4]PF6 (A) (20 mol%), while Cu(II) salts
Finally, metal-free oxidative C–H aminations15 have shown sp2-C–H were generally found to be ineffective. Interestingly, increasing
selectivity for alkyl arene substrates.
the catalyst loading did not improve the yield (Table 1, entries 5, 7
Our pursuit of practical and economical C–H amination and 8). A screen of other first-row transition metal compounds gave
methodologies16 and the cited precedents prompted us to evaluate no/low yields, e.g. 20% using Fe(acac)2 and Fe(OTf)2(CH3CN)2
the efficacy of aminating unactivated arenes by inexpensive (Table S1, ESI†).
copper catalysts and convenient pre-oxidized N-reagents, such
The effect of ligands and other additives on the amination
reaction (eqn (1)) was assessed through screening reactions with
various phosphines, amines, N-heterocycles and acids added to
Cu(AN)4+ + L + TrocNHOTs/benzene (Table S2, ESI†). These revealed
that the best ligands were dppf (57% yield) and neocuproine
(2,9-dimethylphenanthroline, NC) (48%) (Table 1).22 We were
delighted to find that the amination efficiency using NC almost
Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center,
Univ. of Oklahoma, Norman, Oklahoma–73019, USA. E-mail: knicholas@ou.edu;
Fax: +1-405-325-6111, +1-405-325-3696
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data, 1H and 13C spectra. See DOI: 10.1039/c3cc46412a
c
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Table 1 Catalyst variation for the amination of benzenea
Entry
[Cu]/ligand loading (mol%)
Conversiond (%)
Yieldd (%)
1
Cu(TC) (20)
73
—
—
16
10
40
11
2
Me2SꢁCuBr (20)
3b
4
Cu2O (10)
Cu(OTf)2 (20)
35
5
6
7
8
[Cu(CH3CN)4](PF6) (A) (20)
{Cu(OTf)}2ꢁtoluene (10)
A (30)
95
50
100
38
45
20
40
17
A (100)
Fig. 2 Kinetic isotope and substituent effects.
9
A + dppf (20%)
100
64
100
100
57
25
48
75 (57)
10
11
12c
A + phenanthroline (20%)
A + Neocuproine (20%)
A + Neocuproine (20%)
of steric effects with the bulky tert-butyl group blocking ortho-
functionalization. On the other hand the electron-rich arene
anisole, showed regioselectivity more typical of an electrophilic
substitution (ortho > para > meta), while the electron-poor
chlorobenzene produced an equimolar mixture of the three
regioisomers. This contrasts with the selectivity observed for
copper catalyzed aminations with TsNQIPh, which furnished
only ortho/para isomers with anisole and chlorobenzene.11a,12
With electron poor trifluorotoluene, a modest yield of ca. 20%
was obtained, favouring the meta-isomer. The conditions,
yields and regioselectivities observed with the TrocNHOTs–
NC–Cu+ system are comparable to the best observed with other
[M]/N-reagents for amination of simple arenes.10–13
a
Reaction conditions: tosyloxycarbamate (0.138 mmol), [Cu]
(0.027 mmol) and ligand (0.027 mmol) in benzene (ca. 0.5 mL) at 140 1C
in sealed tube for 16 h. b After 48 h. Reaction carried out in ca. 1 mL
c
benzene. d Conversion and yield based on 1,3,5-trimethoxybenzene as an
NMR reference. dppf = diphenylphosphinoferrocene, neocuproine (NC) =
2,9-dimethylphenanthroline.
doubled (ca. 75% yield) when the reaction solvent volume was
doubled.
(2)
To gain insight into the nature of the reactive species in the
reaction, several mechanistic probes were applied. A kinetic
isotope effect (KIE) study using an equimolar amount of
benzene and benzene-d6 exhibited a marginally inverse KIE of
0.9 (ꢀ0.1) (Fig. 2), indicating that C–H bond-breaking is not
involved in the rate limiting step. This contrasts with many
metal promoted C–H functionalization processes, which often
display large primary isotope effects.23
Relative reactivity studies were carried out through competi-
tion experiments with an equimolar mixture of each of several
arenes with benzene to establish the electronic nature of the
reaction. The electron rich arenes, toluene and anisole, were
found to react faster than benzene, krel of 3.2 and 7.2, suggestive of
electrophilic character for the intermediate effecting their amination.
The subdued reactivity of tert-butylbenzene may be due to the
limited accessibility of the ortho positions. Surprisingly, the
electron-poor chlorobenzene was also found to react faster than
benzene (krel. = 8.8). A Hammett plot of kAr–X/kbenz vs. sp values
for these substrates was thus non-linear (Fig. 3), suggestive of a
Having established effective benzene amination using
the A–NC system, we proceeded to extend the method to other
non-directing arenes (eqn (2), Fig. 1). Typically, a mixture of
Troccarbamate (0.14 mmol) and A–NC (20 mol%) in the neat
arene (ca. 1 mL) was stirred at 140 1C for 8 h to produce
regioisomeric mixtures of the aminated arenes.§¶ The alkyl
arenes, toluene and ethylbenzene, were successfully converted
to their regioisomeric aromatic carbamates in good (59%) and
moderate (44%) yields, respectively. Significantly, the reaction
was highly chemoselective with no benzylic amination (Csp3–H)
detected. In contrast the prior [Cu]/PhIQNTs systems give only
benzylic amination products with alkyl arene substrates, while
the [Fe]/PhIQNTs system results in benzylic and aromatic
amination.13 The isomer distribution for toluene showed the
ortho-isomer dominating (ca. 50%) with lesser but nearly equal
amounts of the meta- and para isomers. The toluene reaction also
produced some alkyl arene dimers resulting from Csp2–Csp3 homo-
coupling, while acetophenone, resulting from benzylic C–H oxida-
tion, was detected with ethylbenzene.8 With tert-butylbenzene only
the meta- and para products were observed, probably the result
Fig. 1 Arene amination yields and (o,m,p) regioselectivity.
10966 Chem. Commun., 2013, 49, 10965--10967
Fig. 3 Hammett plot of relative arene reactivity vs. sp.
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Notes and references
‡ Aminated toluene products derive from copper mediated decomposi-
tion of the N-reagent; these were detected with all arene substrates.
§ Sample procedure: to a stirred mixture of A (0.010 g, 0.026 mmol)
and NC (0.005 g, 0.024 mmol) in the arene (ca. 1 mL) was added
N-tosyltroccarbamate (0.050 g, 0.138 mmol) and the mixture was
allowed to stir at 140 1C for 8 h. The reaction mixture was cooled to
room temperature, filtered through a pad of silica washing with CH2Cl2
and the filtrate concentrated under vacuum. The residue was purified
by silica chromatography using 5–15% Et2O in hexanes to obtain the
regioisomeric mixture of aminated arenes. The isomer ratio was deter-
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This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 10965--10967 10967