Beyond Directed ortho Metalation: Ruthenium-Catalyzed Amide-Directed CAr-OMe Activation/Cross-Coupling Reaction of Naphthamides with Aryl Boronates

Article abstract of DOI:10.1021/acs.orglett.5b01913

A new and general synthetic methodology for the construction of biaryl, heterobiaryl, and polyaryl molecules by the ruthenium-catalyzed cross-coupling of ortho-methoxy naphthamides with aryl boroneopentylates is described. The isomeric 1-MeO-2-naphthamides and 2-MeO-1-naphthamides furnish an expansive series of arylated naphthamides in excellent yields. Competition experiments showed the higher reactivity of 1-MeO-2-naphthamide over 2-MeO-benzamide. Orthogonality between the C-O activation/cross-coupling and the Suzuki-Miyaura reactions was established. The method provides naphthalenes which are difficult to prepare by directed ortho metalation.

Full text of DOI:10.1021/acs.orglett.5b01913

Letter
pubs.acs.org/OrgLett
Beyond Directed ortho Metalation: Ruthenium-Catalyzed Amide-
Directed CAr−OMe Activation/Cross-Coupling Reaction of
Naphthamides with Aryl Boronates
Yigang Zhao and Victor Snieckus*
Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, ON K7L 3N6, Canada
S
* Supporting Information
ABSTRACT: A new and general synthetic methodology for the
construction of biaryl, heterobiaryl, and polyaryl molecules by the
ruthenium-catalyzed cross-coupling of ortho-methoxy naphthamides
with aryl boroneopentylates is described. The isomeric 1-MeO-2-
naphthamides and 2-MeO-1-naphthamides furnish an expansive series
of arylated naphthamides in excellent yields. Competition experiments
showed the higher reactivity of 1-MeO-2-naphthamide over 2-MeO-
benzamide. Orthogonality between the C−O activation/cross-
coupling and the Suzuki−Miyaura reactions was established. The
method provides naphthalenes which are difficult to prepare by
directed ortho metalation.
Table 1. Selectivity of Ketone- and Amide-Directed (DG)
C−OMe and C−H Activation/Coupling Reactions
he C−OMe bond of the aryl ether class of organic
molecules is ubiquitous in natural products, pharmaceut-
T
icals, and commodity chemicals. Until recently, the aryl C−
OMe to C−C bond transformation has required prior
conversion into C−OTf, C−OMs, C−OTs, and C−OAc
derivatives followed by use of various cross-coupling protocols.1
In early salient contributions, Wenkert first demonstrated the
direct Corriu−Kumada aryl C−OMe activation/C−C cross-
coupling reaction under Ni(0) catalysis.2 The recent
comprehensive studies3 of Kakiuchi and Chatani have provided
new types of Ru- and Ni-catalyzed C−OMe to C−C bond
conversion of aryl ethers with4 or without5 directing group
(DG) activation. In the Kakiuchi process, both C−H and C−
OMe activation/coupling reactions occur simultaneously to
give 2,6-disubstituted acetophenone products (Table 1, entry 1,
1 → 3).6 In order to avoid the undesired C−H activation,
advantage was taken of steric shielding (entry 2, 1 → 2) or
blocking (using 6-methyl-2-methoxyacetophenone) effects to
obtain satisfactory regioselective C−OMe activation/boroneo-
penylate (Bneop) coupling products.4a Recently, we have
reported7 the catalytic, high yielding, and decidedly regiose-
lective cross-coupling reaction of ortho-anisamides with aryl
Bneop derivatives (entry 3, 1 → 2, DG = CONEt2) driven by
amide group−Ru catalyst chelation.8 Herein we disclose a
general Ru-catalyzed cross-coupling of ortho-OMe naphth-
amides with aryl Bneops (entry 4, 1 → 2, DG = CONEt2). The
methodology (a) constitutes the first systematic Ru-catalyzed
C−O activation/coupling reaction of the naphthalene ring
system;9 (b) provides an efficient protocol for the synthesis of a
variety of arylated naphthalenes which are difficult or
unachievable by the established directed ortho metalation
(DoM)−cross-coupling protocol,10 and (c) establishes an
orthogonal link to the Suzuki−Miyaura cross-coupling reaction.
activation/coupling
entry
DG
substrate via C−H via C−O product
ref
6
1
C(O)Me
phenyl
√
√
√
√
3
3
naphthyl
this
work
2
C(O)t-Bu
phenyl
×
√
−
√
√
2
4a
a
a
a
a
naphthyl
phenyl
−
×
×
−
−
3
4
CONEt2
CONEt2
2
7
naphthyl
2
this
work
a
Not reported.
Interest for the use of this chemistry in the construction of
complex polycyclic aromatics11 may be therefore anticipated.
In the initial test studies, three isomeric ortho-methoxy
naphthamides were examined under the previously established
catalytic RuH2(CO) (PPh3)3 conditions7 which showed that
the yields of cross-coupling products varied as a function of the
methoxy naphthamide isomers (Table 2). Thus, 1-MeO-2-
naphthamide 1a and 2-MeO-1-naphthamide 3a underwent the
C−O activation/cross-coupling reaction to afford the biaryl
Received: July 9, 2015
© XXXX American Chemical Society
A
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Table 2. Ru-Catalyzed C−OMe Activation/Cross-Coupling
Reaction of Isomeric Naphthamides
Scheme 1. Ru-Catalyzed Cross-Coupling Reaction of 1-
a
MeO-2-Naphthamides with Bneops
a
Yields are of isolated and purified products.
products 2a and 4a in excellent yields (entries 1 and 2) while
the 3-MeO-2-naphthamide 5a gave product 6a in a much lower
yield (entry 3). As also observed for the C−O cross-coupling
reactions of benzamides,7 the naphthamides undergo only ortho
C−O activation/coupling reactions and are inert to ortho C−H
bond activation (entries 1 and 3). In contrast, the DG =
C(O)Me naphthalene derivatives give inconsistent results.12
Thus, while the coupling of PhBneop with 2-MeO-1-acetyl-
naphthalene affords 2-phenyl-1-acetylnaphthalene in 84%
yield,4a we find that the isomeric 1-MeO-2-acetylnaphthalene
undergoes both C−H and C−OMe activation processes to give
1,3-diphenyl-2-acetylnaphthalene in quantitative yield.12 Moti-
vated by our comparative results, we investigated the generality
of the reaction of naphthamides 1a and 3a with a variety of aryl
Bneops (Schemes 1 and 2).13
a
b
Yields are of isolated and purified products. Conversion from GC-
MS analysis.
Scheme 2. Ru-Catalyzed Cross-Coupling Reaction of 2-
MeO-1-Naphthamides with Bneops
a
To optimize the conditions, the isomeric 1-MeO-2-
naphthamide and 2-MeO-1-naphthamide were studied in
both diethyl and dimethyl amide series. Thus, as observed for
the conversion of the N,N-diethyl naphthamide 1a → 2a
(Table 2), the corresponding N,N-dimethyl 1-MeO-2-naph-
thamide 1 (R = Me; R′ = H) underwent efficient C−OMe
activation/coupling to afford the biaryl 2b in quantitative yield
(Scheme 1). Furthermore, coupling of 1-MeO-2-CONEt2 and,
in two cases, -2-CONMe2 naphthyl derivatives with ArBneops
bearing Me, CH2Ot-Bu, NMe2, and OMe EDGs (electron-
donating groups) furnished biaryl products 2c−f, 2h−j in good
to excellent yields. Noteworthy is the comparison of couplings
of the N,N-diethyl and N,N-dimethyl 1-MeO-2-naphthamides
with the 2-methylphenyl Bneop derivative to give 2c and 2d
respectively which shows the advantage of using the less
sterically hindered naphthamide. ArBneops with F and CF3
EWGs (electron-withdrawing groups) give the coupled
products 2g, 2k−m in high yields. However, reminiscent of
the results and perhaps the associated rationalization of the
ortho-anisamide studies,7 coupling of naphthamides with
ArBneops bearing CHO and NO2 groups afforded no arylation
products and starting materials were recovered in high yields
(2n and 2o).12a Analogously, a chloro derivative does not serve
for this coupling reaction (2p) possibly due to dehalogenatio-
a
b
Yields are of isolated and purified products. 10 mol % catalyst
loading.
n.12a On the other hand, the reaction of the N,N-diethyl 1-
MeO-2-naphthamide 1 (R = Et; R′ = H) with 2-naphthyl
Bneop smoothly afforded the coupled product 2q in good yield.
Furanyl and thiophenenyl Bneops also furnished the expected
heterobiaryls 2r and 2s in good yields while the pyridin-3-yl
Bneop failed to give the coupled product 2t echoing the studies
with the corresponding ortho-anisamides.7 The (E)-styryl
Bnoep underwent the coupling reaction with both N,N-
dimethyl and N,N-diethyl naphthamides to afford products
2u and 2v in high yields. These results establish a general and
efficient method for the preparation of 1-arylated 2-
naphthamides 2 from the readily available 1 which supersedes
the ineffective method using directed ortho metalation (DoM)
chemistry of the corresponding 2-naphthamide.10f,14 The
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selectivity and steric effects were briefly tested by examination
of several disubstituted-2-naphthamides which were readily
available from the corresponding commercial methoxy
naphthalenes via DoM chemistry (see Supporting Information
(SI)). Thus, the 1,3-dimethoxy-2-naphthamide showed highly
selective 1-OMe coupling to give 2w (structural assignment by
NOESY; see SI), confirming the greater C-1 over C-3 C−OMe
activation reactivity as perhaps already expected from the
observed low yield of product 6a (Table 2, entry 3) obtained
for the coupling of 3-methoxy-2-naphthamide. In comparison,
the failure to obtain 1-phenyl-3-methyl-2-naphthamide 2y via
the C−OMe activation/coupling reaction (98% recovery of
starting material, 1-MeO-3-methyl-2-naphthamide) raises an as
yet not understood interplay or juxtaposition of steric and
electronic effects in these reactions which were also observed in
the ortho-anisamide series.7 The formation of 2-naphthamide 2x
reinforces the significance of amide chelation assistance in these
syntheses of new naphthalene derivatives. The ready and
general availability of coupled products 2 anticipates the
potential of further useful DoM and DreM (Directed remote
Metalation) chemistry.10c,d,f As indicated by the observed high
yields in all reactions, a C−H peri-hindrance effect pertinent to
naphthalenes does not inhibit the C−OMe activated/C-1
coupling.15 More importantly, its synthetic value is underscored
by the fact that the meager literature on N,N-diethyl 2-
naphthamide metalation reactions shows that these derivatives
undergo facile C-1 addition of RLi bases which prevents their
use in the DoM−Suzuki cross-coupling protocol.10f,14
distribution of resonance energy stabilization per ring of
naphthalene (benzene = 36 kcal/mol; naphthalene = 61 kcal/
mol).16
Scheme 3. Competition Experiment between 2-MeO
Benzamide and 1-MeO-2-Naphthamide in Ru-Catalyzed
Cross-Coupling with PhBneop
We then turned our attention to application of the ortho-
methoxy naphthamide C−OMe activation/coupling chemistry.
Considering that the presence of the electron-donating OMe
group in these substrates provides the opportunity to establish
orthogonal cross-coupling strategies,5,7,17 we explored a
sequential bromination, Suzuki−Miyaura cross-coupling, and
Ru-catalyzed C−OMe activation/coupling process for con-
struction of teraryls in two typical isomeric naphthamide series
(Scheme 4). Thus, the selective electrophilic bromination of 1a
Scheme 4. Synthesis of Biaryls and Teraryls via Sequential
Bromination, Suzuki−Miyaura Cross-Coupling, and Ru-
Catalyzed C−OMe Activation/Coupling Reactions
Next, we investigated the generality of the reaction of 2-
MeO-1-naphthamides by systematic variation of the ArBneop
coupling partner (Scheme 2). Based on the favorable effect of
using DG = CONMe2 rather than DG = CONEt2 in the
isomeric series 4a and 4b and the potential greater steric
conflict between the peri-C−H and a 1-amide group, 2-MeO-
N,N-dimethyl-1-naphthamide was employed in the initial study.
As gleaned from Scheme 2, the tolerance of functional groups
present in the Bneop systems is quite similar to that observed in
the 1-MeO-2-naphthamide series. Thus, Me, NMe2, and OMe
EDGs and F and CF3 EWGs gave high yields of biaryl products
4c−d, 4f−k. Furthermore, 2-naphthyl-, thiophenen-3-yl-, and
styryl-Bneops also afforded biaryls 4l−n in excellent yields. Also
similarly, steric hindrance decreased the coupling efficiency
although inconsistently since sterically congested Bneops failed
to afford any C−O activation/coupling products 4e and 4p
while an excellent yield of 4c was obtained in the coupling
reaction with 2-methylphenyl Bneop. Since we found that the
prototype coupling reactions of CONEt2 and CONMe2
systems are equally efficient, the general use of the former
amides to allow further DoM has validity. The now expected
ortho-selective coupling of 2,3-dimethoxy-1-naphthamide, read-
ily available from the corresponding commercial 2,3-dimethoxy-
naphthalene via DoM chemistry, was observed to give a
quantitative yield of 4o (structure confirmed by NOESY; see
SI), a molecule poised for further DoM and DreM
reactions.10c,d,f The comparative evaluation of this synthesis of
2-arylated-1-naphthamides to the DoM−Suzuki protocol
remains to be established due to lack of data on the latter route.
As a qualitative evaluation of relative reactivity, a competition
experiment between 2-MeO-N,N-diethylbenzamide 7a and 1-
MeO-N,N-diethyl-2-naphthamide 1a in the cross-coupling with
PhBneop was carried out and showed that naphthalene ring
activation is significantly greater than that of the benzene ring
(Scheme 3), possibly a reflection of the well-known unequal
quantitatively furnished a single product 9 which, when
subjected to Suzuki−Miyaura coupling with two commercially
available aryl boronic acids, afforded 10 and 11 respectively also
in quantitative yields. Their Ru-catalyzed C−OMe activation/
PhBneop cross-coupling reactions proceeded efficiently to give
1,4-diaryl naphthamides 12 and 13 respectively. This efficient
and operationally simple synthetic route to teraryl derivatives
proceeds in three steps and >94% overall yield. The same
sequence on the isomeric N,N-diethyl and N,N-dimethyl
naphthamides 3a and 3b proceeded via the expected 6-
bromo 14 and 15 and the corresponding 6-para-anisyl 16 and
17 derivatives to afford the 2,6-diaryl naphthamides 18 and 19
respectively in high yields. These orthogonal coupling routes to
C
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teraryls with a functionalized central naphthalene core are of
potential interest in materials science research.18
REFERENCES
■
(1) Reviews: (a) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.;
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In summary, we have demonstrated the first catalytic tertiary
amide-directed C−OMe activation/C−C cross-coupling reac-
tion in the ortho-methoxy naphthamide series for the synthesis
of biaryl and heterobiaryl molecules. The new Ru-catalyzed
methodology is general, efficient, and operationally simple;
requires no additional ligands or base; and encompasses the
following features: (a) the starting ortho-methoxy naphtha-
mides are readily available from simple and inexpensive
commodity chemicals (see SI); (b) compared to the salient
Kakiuchi ketone-directed coupling reaction,4a,6 the amide DG
activation is highly C−OMe regioselective without competitive
C−H activation process interference and provides products
with amide functionality which is more amenable to synthetic
operations compared to the acetyl or pivaloyl groups; (c) it has
the advantages of the powerful DMG (directed metalation
group), CONEt2, which sets the stage for regioselective DoM,
DreM, and combined DoM−Suzuki coupling chemistries10,19
to be effected either pre- or post- the C-OMe activation/
coupling reactions; (d) it allows further useful manipulation by
the efficient method for amide to aldehyde conversion using an
in situ Schwartz reduction recently developed in our
laboratories;20 (e) it provides aryl naphthamides (e.g., 2a−m,
2q−s, 2u−v, 2x, Scheme 1) which are difficult or impossible to
prepare by the combined DoM−Suzuki coupling protoco-
l;10a,b,e (f) it allows links to DreM syntheses of fused fluorenone
and phenanthrol molecules;10c,d and (g) it lends to new
synthetic concepts for orthogonal C−O activation and Suzuki
cross-coupling sequences as exemplified by the preparation of
teraryls (Scheme 4).
(6) Ueno, S.; Kochi, T.; Chatani, N.; Kakiuchi, F. Org. Lett. 2009, 11,
855.
(7) Zhao, Y.; Snieckus, V. J. Am. Chem. Soc. 2014, 136, 11224.
(8) The amide group exhibits greater coordinating ability than the
ketone group; see: Kaye, G. W. C.; Laby, T. H. Tables of Physical and
Chemical Constants, 16th ed.; Longman: New York, 1995.
(9) All previous coupling studies focus on phenyl ring systems; see
refs 4 and 7. A single example of a naphthalene derivative, 2-MeO-1-
acetylnaphthalene, has been reported; see ref 4a.
(10) (a) Snieckus, V.; Anctil, E. J. G. In Metal-Catalyzed Cross-
Coupling Reactions and More; de Meijere, A., Brase, S., Oestreich, M.,
Eds.; Wiley: Weinheim, 2014; Vol. 3, p 1067. (b) Board, J.; Cosman, J.
L.; Rantanen, T.; Singh, S. P.; Snieckus, V. Platinum Met. Rev. 2013,
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Transformations; Dyker, G., Ed.; Wiley: Weinheim, 2005; Vol. 1, p
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Chem. Rev. 1990, 90, 879.
These efforts on the Ru-catalyzed C−O activation/coupling
reactions are aimed to complement and arguably eventually to
supersede our DoM−cross-coupling methodology.10a,b The
present method and related work7,20 has the distinct advantages
over the widely practiced DoM strategy of nonrequirement of
cryogenic temperatures and strong bases which augurs well for
its broader application to provide unusually substituted and
unavailable biaryl and polyaryl derivatives.
(11) (a) Harvey, R. G. Polycyclic Aromatic Hydrocarbons; Wiley: New
York, 1997. (b) For large PAHs, see: Feng, X. L.; Pisula, W.; Mullen,
K. Pure Appl. Chem. 2009, 81, 2203.
(12) (a) Zhao, Y. Ph.D. Thesis, Queen’s University, Kingston,
Ontario, Canada, 2010. (b) See Supporting Information.
(13) Arylboronic acid and its pinacol ester were tested in our Ru-
catalyzed amide-directed C−N activation/coupling chemistry (see ref
12a and Zhao, Y.; Snieckus, V. Org. Lett. 2014, 16, 3200. ) and found
to be unsuccessful. Based on these observations, we did not attempt
analogous C−O activation/coupling reactions, since the boroneopen-
tylate (Bneop) reactions were found to proceed in high yields. (b) In
amide-directed C−OMe activation/coupling reactions, use of
pinacolone as a solvent afforded low yields of products.
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3181.
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(16) Wheland, G. W. Resonance in Organic Chemistry; Wiley: New
York, 1955; p 830.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01913.
Experimental procedures and analytical data for new
compounds and products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
(17) (a) Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed. 2009, 48,
3565. (b) Antoft-Finch, A.; Blackburn, T.; Snieckus, V. J. Am. Chem.
Soc. 2009, 131, 17750.
(18) For very recent work, see: Filo, J.; Misicak, R.; Cigan, M.; Weis,
M.; Jakabovic, J.; Gmucova, K.; Pavuk, M.; Dobrocka, E.; Putala, M.
Synth. Met. 2015, 202, 73.
(19) (a) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew.
Chem., Int. Ed. 2004, 43, 2206. (b) Tilly, D.; Magolan, J.; Mortier, J.
Chem. - Eur. J. 2012, 18, 3804.
(20) (a) Zhao, Y.; Snieckus, V. Org. Lett. 2014, 16, 390. (b) Zhao, Y.;
Snieckus, V. A. U.S. Patent 8,168,833, 2012.
*E-mail: snieckus@chem.queensu.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to NSERC Canada (Discovery Grant) for
continuing support of our synthetic programs, Dr. Francoise
Sauriol (Queen’s University) for assistance with NMR
spectroscopy, and Dr. Jiaxi Wang (Queen’s University) for
discussion of the MS.
D
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