Beyond directed ortho metalation: Ruthenium-catalyzed amide-directed C Ar-N activation/C-C coupling reaction of anthranilamides with organoboronates

Article abstract of DOI:10.1021/ol501180q

A new, catalytic, and general methodology for the synthesis of biaryls and heterobiaryls by the cross coupling of anthranilamide derivatives (o-NMe ₂ benzamides) with aryl boroneopentylates is described. The reaction proceeds under catalytic RuH₂(CO)(PPh₃)₃ conditions driven by the activation of the unreactive C-N bond by amide directing group (DG)-Ru catalyst chelation. High regioselectivity, orthogonality with the Suzuki-Miyaura reaction, operational simplicity, and convenient scale-up are features of these reactions which may lend themselves to industrial applications.

Full text of DOI:10.1021/ol501180q

Letter
pubs.acs.org/OrgLett
Beyond Directed Ortho Metalation: Ruthenium-Catalyzed Amide-
Directed CAr−N Activation/C−C Coupling Reaction of
Anthranilamides with Organoboronates
Yigang Zhao and Victor Snieckus*
Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, Ontario K7L 3N6, Canada
S
* Supporting Information
ABSTRACT: A new, catalytic, and general methodology for
the synthesis of biaryls and heterobiaryls by the cross coupling
of anthranilamide derivatives (o-NMe2 benzamides) with aryl
boroneopentylates is described. The reaction proceeds under
catalytic RuH2(CO)(PPh3)3 conditions driven by the
activation of the unreactive C−N bond by amide directing
group (DG)-Ru catalyst chelation. High regioselectivity,
orthogonality with the Suzuki−Miyaura reaction, operational
simplicity, and convenient scale-up are features of these
reactions which may lend themselves to industrial applications.
activation reaction, consistent also with the requirements for
lthough still in nascent development, the area of activation
Aof unreactive C−H, C−O, and C−N bonds mediated by C−H and C−OMe activation processes,5,6 chelation assistance
from an anchoring ketone directing group (DG)7 was
transition-metal catalysis promises to greatly enrich the toolbox
of synthetic organic chemists.1 Amines constitute one of the
established as the significant initial event of the highly efficient
C−NMe2 activation/organoboronate cross coupling reactions
(Table 1, DG = C(O)Me and C(O)-t-Bu).
most prevalent and unreactive classes of organic compounds,
among which the arylamines have particularly high C−N bond
dissociation energy2 whose cleavage usually invokes conversion
to more reactive leaving groups3 such as diazonium salts,3a−c
ammonium salts,3d−h triazenes,3i azoles,3j and arylhydrazines.3k
Although scattered observations of aniline C−N bond cleavage
had been reported,3d−h,k,4 it was the discovery of Kakiuchi in
2007 which provided the first, catalytic C−N coupling reaction
of o-NMe2 substituted pivalophenones with organoboronates
under RuH2(CO)(PPh3)3-catalyzed conditions1g (Table 1),
parallel to their equally important original findings of the aryl
C−OMe bond activation−cleavage process in the correspond-
ing o-OMe substituted aryl ketones.5 In the Kakiuchi C−NMe2
Motivated by these findings, we proposed that the tertiary
amide CONEt2, a powerful directed metalation group (DMG),
widely exploited in directed ortho metalation (DoM) synthetic
strategies,8 may offer a chelating DG consequence for C−H,
C−O, and C−N bond activation/cross-coupling reactions
based on the following rationale: the CONEt2 group should
exhibit greater coordinating ability than esters and ketones,9
DGs whose activation of these bonds has been established;
although two different reaction types are compared, the well-
known steric bulk of CONEt2 in DoM chemistry in resisting
nucleophilic attack by organolithium reagents suggested that it
would exhibit properties similar to those of the tert-butyl group
in o-NMe2/OMe-pivalophenones in preventing nonregioselec-
tive C−H, C−O, and C−N activation and, therefore,
diarylation.1g,5
Table 1. Selectivity of Ketone- and Amide-Directed C−
NMe2 and C−H Activation/Coupling Reactions
In pursuit of demonstration of these objectives, we have
recently achieved the Ru-catalyzed N,N-diethyl o-OMe
benzamide (o-anisamide)/aryl boronate cross-coupling reac-
tion.10 Coincident with these studies, we initiated work on the
corresponding o-NMe2 benzamide/aryl boronate coupling
(Table 1, DG = CONEt2) and herein report our preliminary
results. We demonstrate that the DG = CONEt2 serves
effectively for C−NMe2 activation in the Ru-catalyzed cross
coupling with aryl boroneopentylates (ArBneop), thus
Received: April 23, 2014
© XXXX American Chemical Society
A
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Letter
providing a new general methodology which (a) displays all the
advantageous attributes of the regioselective DoM strategy in
pre- and postcoupling modes; (b) offers complementarity to
the DoM reaction in a process that avoids cryogenic
temperatures and strong base conditions; (c) is amenable to
orthogonal cross coupling variation;11 and (d) provides
opportunity for ready amide to other functional group
conversions.12 Combined, these features offer new promising
opportunities for synthetic aromatic chemistry.
Scheme 1. Ru-Catalyzed Cross Coupling Reaction of o-NMe2
Benzamides with Bneops
a,b
In the prototype experiment, treatment of N,N-diethyl o-
NMe2 benzamide (anthranilamide) with PhBneop under
conditions similar to those applied in the o-anisamide reaction10
afforded the diphenyl amide 2a (Table 2) in quantitative yield
Table 2. Screening Amino Groups for the Cross-Coupling
Reaction of o-Amino Benzamides with PhBneop
a
b
Yields are of isolated and purified products. Yield determined by
GC−MS analysis; PhNHMe was also formed in 11% yield (GC).
c
Starting material recovery (95%).
a
b
Yields are of isolated and purified products. Equivalents of
boroneopentylates/reaction times in hours are shown in parentheses.
in a 1 h reaction time with no detectable product of alternative
C−H activation/cross coupling. As established also in the o-
anisamide coupling reaction,10 the significance of DG-chelation
assistance was demonstrated by treatment of N,N-diethyl 3- and
4-NMe2 benzamides with PhBneop for an extended time (20 h)
which resulted in recovery of starting material with <4%
detection of phenylated products (GC−MS analysis, see the
SI). Similar to our observations for the C−OMe activation/
coupling reactions13 and as reported by Kakiuchi,5 aryl
boroneopentylates appear to be unique in reactivity as the
corresponding boropinacolates and boronic acids failed to give
C−N activation/cross coupling products (SI). To obtain
appreciation of amide N-substitution steric effects, N,N-
diisopropyl o-NMe2 benzamide was tested and found, even
under 3 h refluxing toluene conditions, to give the
corresponding 2-phenyl derivative 2b in much decreased
(48%) yield (Scheme 1). N,N-Dimethyl benzamides were not
considered in view of their ineffectiveness in DoM chemistry.14
Brief examination of N-2-amino substitution (Table 2)
showed that the bulky 2-N(Me)Ph group inhibited the reaction
leading to the corresponding 2-phenyl-coupled product 2a in
only 44% yield after a 20 h reaction time and also to the
formation of byproduct PhNHMe (11% yield), as direct
evidence of reductive deamination. When N,N-diethyl 2-NH2
benzamide was subjected to the coupling reaction conditions,
starting material was recovered in quantitative yield, in contrast
c
d
10 mol % catalyst loading. cis or trans stereochemistry not
1
established by H NMR due to almost identical Jcis and Jtrans coupling
constants19 and unavailability of crystalline material for X-ray analysis.
to the observations in ketone-directed C−N activation/
coupling in which 2-NH2 (and 2-NHMe) did not prevent
efficient aryl coupling.1g Thus, it appears that minimal steric
hindrance and unavailability of N−H bonds are important
requirements to achieve a highly efficient amide-directed C−N
activation/cross-coupling result.
To complete our screening experiments, optimum temper-
atures for short reaction time (130 °C/1 h) and boroneo-
pentylate reactant (1.05 equiv) and RuH2(CO)(PPh3)3 catalyst
(4 mol %) stoichiometries were determined (SI). With these
control and structural parameters in hand, we proceeded to test
the generality of the reaction with a variety of aryl
boroneopentylates. The results are shown in Scheme 1 and
deserve comment. First, the coupling reaction proceeds mostly
in excellent yields for EDGs (electron-donating groups) such as
Me, CH2O-t-Bu, NMe2, and OMe (2c−h, Scheme 1).
However, EWGs (electron-withdrawing groups) showed a
range of effects. When F- and CF3-bearing aryl Bneops were
employed, the coupling reaction proceeded in high yields (2i−
l). However, when CHO-, CN-, and NO2-substituted ArBneops
were used, the arylation was completely inhibited even after a
B
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Letter
20 h reaction time (SI).15 While CHO-, CN-, and NO2-
substituted ArBneops were not studied in the o-NMe2
pivalophenones by Kakiuchi, these workers also observed, as
part of an insightful mechanistic study, a similar higher
reactivity of the corresponding CF3-arylBneop derivative
which was attributed to an accelerating effect of the amido
Ru species−arylboronate transmetalation step due to higher
Lewis acidity at the boron atom.7b,16 Similar to our results for
the o-OMe aryl amide C−O activation/arylation reaction,13
chloro- and bromo-ArBneop derivatives were found not to
undergo this coupling reaction (SI) possibly due to hydro-
dehalogenation which was not studied in the C−O and C−N
pivalophenone series.1g,5 The naphthalen-2-ylboroneopentylate
was found to afford the arylated product 2m in high yield, and
the thiophenenyl, furanyl, and benzofuranyl Bneop derivatives
gave good yields of products 2n−p using a slight excess of
boronates and prolonged reaction times (Scheme 1). When a
sterically congested boroneopentylate was employed, the
expected coupled product 2t was not detected, and
deboronation and reductive de-NMe2 became the major
reactions. The (E)-styrylBneop underwent arylation to give
the stilbene product 2q in modest yield. Two alkyl
boroneopentylates were tested: while n-butyl Bneop failed to
undergo the coupling reaction to form product 2s (isolation of
starting material), cyclopropyl Bneop afforded the interesting
derivative 2r. It appears that, in contrast to a single case
reported for the 2-amino pivalophenone,1g a 2-amino
Scheme 3. Synthesis of Teraryls via Sequential Bromination,
Suzuki−Miyaura Cross-Coupling, and Ru-Catalyzed C−
NMe2 Activation/Coupling Reactions
overall yield in three steps. This may be considered as a
prototype sequence for extension to tandem catalysis, tailor-
made ligand design and construction,20 and defined π-
conjugated oligomer synthesis.21
In summary, the first catalytic amide-directed C−N
activation/C−C bond-forming reaction for the synthesis of
biaryls and heterobiaryls has been demonstrated. Similar to the
Ru-catalyzed o-anisamide/aryl boroneopentylate cross-coupling
process,10 the corresponding, readily derived22 N,N-diethyl o-
NMe2 benzamide/cross-coupling reaction is general, robust,
and proceeds with high efficiency and regioselectivity
uncompromised by the competitive C−H activation/cross-
coupling reaction as observed for the corresponding o-NMe2
acetophenone derivatives.1g Coupled with the standard
Suzuki−Miyaura protocol, it has advantages of orthogonal
reaction sequences and may be exploited in DoM and DreM
(directed remote metalation)8 chemistry prior23 or post to the
C−N cross-coupling event for the construction of more highly
substituted and polycondensed aromatic derivatives (Figure 1,
3
benzamide/Csp boroneopentylate coupling reaction fails in
both oxidative addition and transmetalation steps as evidenced
by quantitative isolation of starting amide. The successful
behavior of the cyclopropyl Bneop coupling reaction may be
2
partially attributed to the established Csp character of the
cyclopropyl C−H bonds17 but is perhaps surprising in view of
the ring-opening reactivity of cyclopropyl derivatives with low-
valent transition metals.18
In order to qualitatively obtain a direct reactivity comparison
between the C−N and C−O bond activation/cross-coupling
reactions, a competitive experiment was carried out using a
1:1:1 mixture of N,N-diethyl o-NMe2 benzamide 1, N,N-diethyl
o-OMe benzamide 3, and PhBneop (Scheme 2). The result,
Scheme 2. Competition Experiment for the C−N and C−O
Activation/Cross-Coupling Processes
Figure 1. Synthetic potential of combined C−NMe2 activation/cross
coupling−DoM−DreM chemistry.
A and B). Of greatest significance, the N,N-diethyl o-NMe2
benzamide/ArBneop cross-coupling reaction presents a new
catalytic methodology for the synthesis of biaryl- and
polyarylamides which complements the stoichiometric DoM−
Suzuki−Miyaura cross-coupling two-step combination24 but
proceeds under noncryogenic temperatures and without use of
strong organolithium bases. In view of these features, the
application of the coupling reaction for convenient and effective
new synthetic methodology may be anticipated.
indicating that C−N activation is faster than C−O activation, is
consistent with the short reaction times required for the C−N
coupling process compared to that of the corresponding C−O
reaction.10
As demonstrated in the N,N-diethyl o-anisamide/ArBneop
coupling studies,10 advantage may be taken of the expected
high SEAr reactivity of the N,N-diethyl 2-NMe2-benzamide
derivatives for devising orthogonal cross coupling chemistry11a
(Scheme 3). In this pursuit, treatment of N,N-diethyl o-NMe2
benzamide with NBS gave the bromobenzamide 2 which, upon
standard Suzuki−Miyaura cross-coupling conditions, afforded
the biaryl 3. Subjection of 3 to the Ru-catalyzed coupling
procedure using p-anisyl Bneop provided the teraryl 2h in 80%
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and analytical data for new com-
pounds and products. This material is available free of charge
via the Internet at http://pubs.acs.org.
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Silberstein, A. L.; Komaromi, A.; Blackburn, T.; Ramgren, S. D.; Houk,
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(12) For amide to aldehyde conversion using the Schwartz reagent,
see: (a) Zhao, Y.; Snieckus, V. Org. Lett. 2014, 16, 390. (b) Zhao, Y.;
Snieckus, V. US 8,168,833, 2012. For other transformations of amides,
see: (c) Larock, R. C. Comprehensive Organic Transformations. A Guide
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(13) Zhao, Y. Ph.D. Thesis, Queen’s University, Kingston, ON,
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(14) (a) Beak, P.; Brown, R. A. J. Org. Chem. 1982, 47, 34. (b) Ludt,
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(15) These substituent effect trends are quite similar as those found
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(16) Sivaev, I. B.; Bregadze, V. I. Coord. Chem. Rev. 2014, 270−271,
75.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: snieckus@chem.queensu.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to NSERC Canada for support of our synthetic
efforts under the Discovery Grant (DG) program and thank Dr.
Francoise Sauriol (Queen’s University) for assistance in NMR
spectroscopy and Dr. Jiaxi Wang (Queen’s University) for
discussion of MS.
(17) Wiberg, K. B. Acc. Chem. Res. 1996, 29, 229.
(18) Ruhland, K. Eur. J. Org. Chem. 2012, 2683.
(19) Wang, Q. W.; Mayer, M. F.; Brennan, C.; Yang, F. K.; Hossain,
M. M.; Grubisha, D. S.; Bennett, D. Tetrahedron 2000, 56, 4881.
(20) Nakao, Y.; Chen, J. S.; Tanaka, M.; Hiyama, T. J. Am. Chem. Soc.
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(21) Grimsdale, A. C.; Mullen, K. Macromol. Rapid Commun. 2007,
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(22) From commercial anthranilic acid, see: (a) Clayden, J.; Stimson,
C. C.; Keenan, M. Chem. Commun. 2006, 1393. (b) Kim, Y. K.; Lee, S.
J.; Ahn, K. H. J. Org. Chem. 2000, 65, 7807.
(23) For DoM reactions on N,N-diethyl o-NR2 anthranilamides to
derive useful 1,2,3-trisubstituted aromatics, see: (a) MacNeil, S. L.;
Wilson, B. J.; Snieckus, V. Org. Lett. 2006, 8, 1133. (b) Rios, R.;
Jimeno, C.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
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2a, see: (d) Tilly, D.; Fu, J. M.; Zhao, B. P.; Alessi, M.; Castanet, A. S.;
Snieckus, V.; Mortier, J. Org. Lett. 2010, 12, 68. With few exceptions,
all compounds in Scheme 1 are potentially primed for this as well as
yet unknown metalation chemistry.
(24) (a) Snieckus, V.; Anctil, E. J. G. Metal-Catalyzed Cross-Coupling
Reactions and More; Wiley: New York, 2014; Vol. 3, p 1067. (b) Board,
J.; Cosman, J. L.; Rantanen, T.; Singh, S. P.; Snieckus, V. Platinum
Metals Rev. 2013, 57, 234. (c) Anctil, E. J. G.; Snieckus, V. J.
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