Aniline carbamates: A versatile and removable motif for palladium-catalyzed directed c-h activation

Article abstract of DOI:10.1002/chem.201403712

The aniline carbamate is introduced as a new removable directing group for C-H activation. Its versatility and ability as a directing group are demonstrated by its use in the ortho-arylation of a wide variety of aniline derivatives under palladium(II) catalysis, with symmetric diaryliodonium salts as aryl donors. The reaction differs from previously reported arylations in its selectivity and its mechanism, as elucidated by kinetic and isotopic experiments. The directing group can also be easily removed under a variety of conditions.

Full text of DOI:10.1002/chem.201403712

DOI: 10.1002/chem.201403712
Communication
&
CÀH Activation
Aniline Carbamates: A Versatile and Removable Motif for
Palladium-Catalyzed Directed CÀH Activation
Nick Uhlig and Chao-Jun Li*[a]
bility of late-stage CÀH functionalization of complex mole-
cules.[16]
We envisaged the use of these aniline carbamates as dual
Abstract: The aniline carbamate is introduced as a new
removable directing group for CÀH activation. Its versatili-
ty and ability as a directing group are demonstrated by its
use in the ortho-arylation of a wide variety of aniline deriv-
atives under palladium(II) catalysis, with symmetric diaryl-
iodonium salts as aryl donors. The reaction differs from
previously reported arylations in its selectivity and its
mechanism, as elucidated by kinetic and isotopic experi-
ments. The directing group can also be easily removed
under a variety of conditions.
purpose CÀH activation directing groups: being easily remova-
ble or modifiable, they represent a new possibility for the con-
struction of diverse aniline derivatives; and simultaneously
they represent a commonplace structure in a variety of target
compounds, suggesting utility in late-stage CÀH functionaliza-
tion. Using a palladium(II)-catalyzed ortho-arylation reaction,
we were able to study their reactivity towards CÀH activations.
This represents the first systematic investigation of diverse ani-
line carbamates as substrates for sp2 CÀH activation, includes
a number of mechanistic studies, and serves as a proof-of-con-
cept for their use in other CÀH activations, as well as elucidat-
ing their distinct reactivity and selectivity.
Modern methods for the formation of CÀC bonds focus on the
catalytic activation of CÀH bonds, obviating the need for
chemical groups like halides, triflates, and boronic acids while
instead relying on directing groups for positional selectivity.[1]
Many directing groups have been developed within this con-
text, from the highly effective yet large and irremovable 2-phe-
nylpyridine to smaller and often removable groups such as car-
boxylic acids,[2] alkoxybenzamides,[3] anilides,[4] ureas,[5] and
phenol carbamates.[6] Removal of these directing groups pro-
vides chemists with access to a greater range of possible prod-
ucts, since target compounds are not limited to those contain-
ing the directing group.[7] This strategy has seen extensive use
in total synthesis of active compounds and natural products,
and in diversity-oriented synthesis.[8]
Investigations began using the easily prepared methyl phe-
nylcarbamate (1a), in the presence of palladium(II) acetate and
diphenyliodonium tetrafluoroborate (2a) in toluene at 1008C
(Table 1).[4e] Iodonium salts were selected as aryl donors due to
their stability, low toxicity,[17] ease of synthesis,[18] and preclu-
sion of the need for external oxidants, such as silver(I) salts.
Water was found to be essential for the reaction to reach good
yield (Table 1, entries 2 and 10), and diminishing marginal yield
was seen upon addition of more than 1 equivalent of Ph2I+
À
À
BF4 (Table 1, entry 3). Interestingly, the use of Ph2I+PF6 al-
lowed dramatically improved yield even with a significant re-
duction in temperature (Table 1, entries 5 and 6). Further, it
Phenol carbamates have been investigated as removable CÀ was found that good yields could be achieved by adding
À
H activation directing groups for many transformations, includ-
ing alkenylations,[9] arylations,[4a,6] borylations,[10] halogen-
ations,[4a,11] and oxygenations.[12] However, their isomeric cous-
ins, aniline carbamates, are rarely employed in CÀH activation
literature (Figure 1),[4e,13] despite being chemically similar to
phenol carbamates, and excellent ortho-metalation directors.[14]
Additionally, carbamate functionality is widespread in natural
products, and is found in a wide variety of therapeutic com-
pounds.[15] New methods for the diversification of these struc-
tures are thus highly desirable, and the use of such attractive
target functionalities as directing groups opens up the possi-
a source of the PF6 anion (either KPF6 or HPF6) to the reaction.
This allowed the use of the more easily synthesized diaryliodo-
nium tetrafluoroborate salts (Table 1, entries 7 and 8). However,
KPF6 and HPF6 later proved unacceptable as additives due to
poor reactivity with certain substrates.[18] Addition of the acid
HBF4 offered generally better yields (Table 1, entry 12), and was
chosen as the optimal additive.
[a] N. Uhlig, Prof. Dr. C.-J. Li
Department of Chemistry and FQRNT Centre for
Green Chemistry and Catalysis, McGill University
801 Sherbrooke St. West, Montrꢀal, Quꢀbec, H3A 0B8 (Canada)
E-mail: cj.li@mcgill.ca
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403712.
Figure 1. Carbamate-based CÀH activation directing groups.
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shows good monoselectivity, even in an excess of arylating re-
agent. When two equivalents of iodonium salt were used, full
conversion was reached, with a 4.4:1 ratio of mono- to di-
arylated products (Table 1, entry 13), indicating that while the
reaction is monoselective, the biaryl carbamate products are
viable substrates for further arylation. Inspired by these find-
ings, methyl biphen-2-ylcarbamate (3a) was subjected to
modified arylation conditions with iodonium salt 2d, resulting
in unsymmetric terphenyl product 4b in 61% yield (Scheme 2).
Previous mechanistic studies for similar arylation reactions
focused on the 2-phenylpyridine substrates and found a non-
rate-limiting CÀH activation event.[5d] However, the strong co-
ordination of these substrates likely leads to a different mecha-
nism than for anilides or carbamates, which possess weaker co-
ordinative abilities. To decipher the mechanism, noncompeti-
tive experiments were carried out to determine the intermolec-
ular kinetic isotope effect (KIE; Scheme 3). A KIE of 4.3 was
found, indicating that CÀH activation is indeed involved in the
rate-limiting step of the reaction.
Table 1. Optimization for the arylation of methyl phenylcarbamate 1a.
Entry XÀ
(equiv)
Additive(s)
t [h],
T [8C]
3a
[%][a]
4a
[%]
À
1
2
3
4
5
6
7
8
BF4À (1.0) none
24, 100 45
24, 100 61
24, 100 72
24, 100 35
24, 100 75
0
0
2
0
BF4À (1.0) 10 mL H2O
BF4 (1.5) 10 mL H2O
OTfÀ (1.0) 10 mL H2O
PF6À (1.0) 10 mL H2O
PF6ÀÀ (1.0) 10 mL H2O
BF4À (1.0) 1 equiv KPF6, 50 mL H2O
BF4À (1.0) 1 equiv HPF6(aq.)
0
24, 50
24, 50
24, 50
92
trace
92 (86) trace
63
trace
0
0
9
BF4À (1.0) 1 equiv TFA,[b] 50 mL H2O 24, 50
trace
30
92 (88) trace
(79) (18)
[c]
10
12
13
BF4À (1.0) 1 equiv HBF4
24, 50
18, 50
18, 50
BF4À (1.0) 1 equiv HBF4, 50 mL H2O
BF4 (2.0) 1 equiv HBF4, 50 mL H2O
[a] Yields were calculated by NMR spectroscopy using nitromethane as an
internal standard. Yields in parentheses are isolated ones, and all yields
represent the average of two separate runs. [b] Trifluoroacetic acid.
[c] HBF4·Et2O.
Several other isotopic experiments were run in an effort to
explain the reactivity of substrates under different reaction
conditions (Scheme 4). When d5-1a was arylated with HPF6 as
an additive, lower yield was obtained and H/D scrambling
could be seen at the ortho- and para-positions of the product
3a, indicating a competing electrophilic aromatic substitution
(SEAr). Scrambling on the substrate 1a was also seen with HPF6
in the absence of palladium or arylating reagent. However,
none was seen when KPF6 or HBF4 were used. These observa-
tions indicate that the efficacy of the reaction depends on the
strength of the acid additive used, and in combination with
the KIE data, suggest a rate-limiting electrophilic palladation
mechanism that requires a highly electrophilic palladium
center for good general reactivity.[18]
With a set of simple and relatively mild conditions in hand,
the reaction’s scope was tested on a wide variety of aniline
carbamate derivatives featuring modification on the aryl ring,
the carbamate nitrogen, and the carbamate alkyl chain
(Scheme 1). Most substrates provided good to excellent yields
of the desired products, with some temperature modifications.
Little to no diarylated product was seen in all cases, and regio-
selectivity was excellent, yielding single products for all meta-
substituted carbamate substrates (Scheme 1). Even electron-
deficient arenes gave generally good yields with the exception
of 1q. Interestingly, upon attempted arylation of 1q at higher
temperatures, a small amount of byproduct was observed, aris-
ing from the cross-dehydrogenative coupling (CDC)[19] of the
carbamate with toluene. Using benzene solvent precluded the
formation of this product, producing only the desired 3q in
low yield.
Based on these experiments, the postulated mechanism for
the arylation can be seen in Scheme 5. A highly electrophilic
palladium center is generated by treatment with the added
acid, and performs an electrophilic palladation of the substrate
1a to produce the palladacycle I. Oxidative addition of the di-
aryliodonium salt likely produces a palladium(IV) intermediate
II, which then undergoes reductive elimination to regenerate
the active catalyst and release the product 3a.[18] However, a bi-
metallic PdIII intermediate in place of II is also possible,[4d,25]
and cannot be ruled out.
In testing the reaction’s scope for arylating reagents, unsym-
metrical iodonium salts[5d,e,7b,13e,20–22] proved poor reaction part-
ners for the carbamate substrates, possibly due to steric bulk,
retarding the rate of oxidative insertion by palladium.[23] There-
fore, symmetric iodonium salts[24] were used to investigate the
scope. Good yields were seen with all diaryliodonium sub-
strates (Scheme 1). Despite acidic reaction conditions, both the
directing group and methyl ester (Scheme 1, 3w) were well-
tolerated.
Finally, the removal of the directing group was examined.
Using previously reported alkaline conditions,[26] removal of the
methyl carbamate group could be effected to yield 2-aminobi-
phenyl in 95% isolated yield (Scheme 6). Additionally, ethyl
and phenyl carbamate moieties could be removed very easily
by using TBAF deprotection,[27] the latter after only 5 min at
Notably, this arylation reaction shows exclusive selectivity for
functionalizing sp2 CÀH bonds, even in the presence of sp3 CÀ room temperature. The product of this deprotection, 2-amino-
H bonds. This is in contrast to the selectivity for sp3 CÀH
bonds seen with Boc-protected methylamine derivatives.[13d]
Additionally, phenyl (phenyl)carbamate 1e, a substrate with
both phenol and aniline carbamate functionality, showed com-
plete selectivity for functionalization of the aniline moiety,
rather than the previously established reactivity selective for
the phenol moiety (Scheme 1, product 3e).[6] The reaction also
biphenyl, is itself a useful ligand[28] and directed CÀH activation
substrate.[29]
In summary, we have established a new set of directing
groups based on the aniline carbamate moiety for the aryla-
tion of aniline derivatives, comprising the first investigation of
aniline carbamates as a directing group for sp2 CÀH activa-
tions. The directing group allows arylation of diverse aniline
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lectivity for sp2 CÀH bonds of
the aniline moiety. The arylation
was shown to proceed by a rate-
limiting CÀH activation step,
comprising an electrophilic palla-
dation, the rate of which is
highly dependent on the acid
employed. Further studies on
the use of aniline carbamates as
directing groups for CÀH activa-
tions are ongoing in our labora-
tory.
Experimental Section
Arylation of aniline carba-
mates: general procedure
Under air, carbamate 1a (30.2 mg,
0.2 mmol) was added to an oven-
dried V-shaped microwave vial
equipped with
a
stir vane.
Pd(OAc)2À(2.24 mg, 0.01 mmol) and
Ph2I+BF4 2a (73.6 mg, 0.2 mmol)
were then added, followed by tol-
uene (250 mL), distilled water
(50 mL), and HBF4·Et2O (28 mL,
0.2 mmol). The vial was sealed and
placed in an oil bath at 508C for
18 h. Upon completion, the reac-
tion was diluted with EtOAc
(~2 mL), and quenched with satu-
rated NaHCO3(aq.) (~1 mL). The or-
ganic layer was separated, and the
aqueous layer was extracted with
EtOAc (2ꢁ2 mL). The organic frac-
tions were combined and eluted
through a short plug of silica gel.
The filtrate was evaporated and
the residue was purified by flash
chromatography, with a gradient
elution (hexanes and EtOAC) to
yield 3a as a yellow-white solid
(40 mg, 88% yield).
Scheme 1. Substrate scope for the arylation of aniline carbamate derivatives with a number of symmetrical diaryl-
iodonium salts. Reaction conditions: carbamate (0.2 mmol), diaryliodonium salt (1.0 equiv), Pd(OAc)2 (0.01 mmol),
HBF4·Et2O (1 equiv), toluene (250 mL), H2O (50 mL), at 508C for 18 h unless otherwise noted. All yields are isolated,
and all reactions were run in duplicate. [a] Reaction performed in benzene.
Scheme 2. A second arylation to produce unsymmetrical terphenyls was
also achieved.
carbamates in generally good yields, and can be easily re-
moved to yield 2-aminobiaryls. The reaction shows excellent
Scheme 3. Intermolecular isotopic studies indicate a rate-limiting CÀH acti-
regioselectivity, good monoselectivity, and excellent chemose-
vation.
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Keywords: aniline carbamates · arylation · CÀH activation ·
cross-coupling · palladium
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Acknowledgements
N.U. would like to thank Soumen Kundu, Andrea Renzetti,
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Received: May 28, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
CÀH Activation
N. Uhlig, C.-J. Li*
&& – &&
Aniline Carbamates: A Versatile and
Removable Motif for Palladium-
Catalyzed Directed CÀH Activation
G’day, (carba)mate! A new removable
directing group for sp2 CÀH activation,
the aniline carbamate, is examined in
detail. Its utility as a directing group is
demonstrated by the ortho-arylation of
aniline derivatives under PdII catalysis,
with iodonium salts as aryl donors and
oxidants. Excellent regio- and chemose-
lectivity were observed. The directing
group can also be easily removed to
yield 2-aminobiaryl products (see
scheme).
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!