C-H activation by amide chelation control: Ruthenium-catalyzed direct synthesis of 2-Aryl-3-furanamides

Article abstract of DOI:10.1002/adsc.201400147

A new, catalytic methodology for the synthesis of heterobiaryls by the ruthenium-catalyzed C-H activation/cross-coupling of heterocyclic amides with aryl boroneopentylates is surveyed. From this survey, the highly regioselective reaction of furan-3-carboxamide to give 2-aryl-3-furanamides is optimized and generalized in scope with respect to the aryl boroneopentylate coupling partners. Established thereby is a one-step synthetic method which may supercede the broadly applied two-step directed ortho metalation (DoM)-cross coupling reaction involving cryogenic and strong base conditions and which has potential for further ortho and remote metalation chemistry.

Full text of DOI:10.1002/adsc.201400147

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DOI: 10.1002/adsc.201400147
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C H Activation by Amide Chelation Control: Ruthenium-
Catalyzed Direct Synthesis of 2-Aryl-3-furanamides
Yigang Zhaoa and Victor Snieckusa,*
a
Department of Chemistry, Queenꢀs University, Kingston, ON K7L 3N6, Canada
E-mail: snieckus@chem.queensu.ca
Received: February 9, 2014; Revised: March 31, 2014; Published online: April 30, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400147.
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Abstract: A new, catalytic methodology for the syn-
tempts for C H activation/arylation of N,N-diethyl-
benzamides afforded only trace amounts of prod-
ucts,[7] heterocyclic tertiary amides provided encour-
aging results. Herein we report on the exploration of
thesis of heterobiaryls by the ruthenium-catalyzed
ꢀ
C H activation/cross-coupling of heterocyclic
amides with aryl boroneopentylates is surveyed.
From this survey, the highly regioselective reaction
of furan-3-carboxamide to give 2-aryl-3-furan-
ꢀ
C H reactivity of selected p-excessive and p-deficient
heteroaromatic tertiary amides and, specifically, on
N,N-diethylfuran-3-carboxamide as a special hetero-
cycle which participates in general and efficient Ru-
ACHTUNGTRENNUNGamides is optimized and generalized in scope with
respect to the aryl boroneopentylate coupling part-
ners. Established thereby is a one-step synthetic
method which may supercede the broadly applied
two-step directed ortho metalation (DoM)–cross
coupling reaction involving cryogenic and strong
base conditions and which has potential for further
ortho and remote metalation chemistry.
ꢀ
catalyzed C H activation/ArBneop cross coupling re-
actions (Scheme 1). These results and their synthetic
consequences related to directed ortho metalation
(DoM) chemistry provide new opportunities in syn-
thetic heterocyclic chemistry.[3]
Noting the not markedly different bond dissociation
energies (BDEs) of heterocyclic systems compared to
that of benzene,[8] we undertook, with the appropriate
caveat regarding the interpretation of BDEs, screen-
ing of a variety of heterocyclic tertiary amides, many
of which are available in our laboratories from ongo-
ing DoM research. Following the standard conditions
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Keywords: amides; C H activation; chelation con-
trol; cross-coupling; furans; ruthenium
Transition metal-catalyzed reactions based on activa-
ꢀ
ꢀ
ꢀ
tion of inert C H, C O, and C N bonds are rapidly
achieving prominence in the synthetic chemistꢀs tool
box.[1] Recently, inspired by the prominent work of
Murai and Kakiuchi,[2] we disclosed new synthetic
ꢀ
ꢀ
methodologies based on Ru-catalyzed C O and C N
bond regioselective cross-coupling reactions of ortho-
OMe and ortho-NMe2 substituted aromatic amides
and esters with aryl boroneopentylates (ArBneops),
and, per ipsum, links to and complements of the di-
rected ortho metalation (DoM) strategy,[3] for the con-
struction of substituted biaryls and heterobiaryls.[4]
ꢀ
ꢀ
Our success in C O and C N activation/coupling by
amide directing group (DG) chelation[4] and the nota-
ble achievement by the Kakiuchi group of ketone-di-
[5]
ꢀ
rected C H activation/coupling (Scheme 1) motivat-
ed consideration, in parallel studies, the prospect of
observing pure C H activation events in aromatic ter-
ꢀ
ꢀ
Scheme 1. Aryl ketone- and amide-directed C H activated
Ru-catalyzed cross-coupling reactions with arylneopenty-
tiary amide derivatives due to the greater coordina-
tion ability[6] of amides over ketones. Although at- lates.
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Yigang Zhao and Victor Snieckus
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Table 1. Investigation of C H activation/arylation reactivity of heteroarylamides.
[a]
Yields of isolated and purified products.
1.1 equiv. of PhBneop were employed.
Reaction time: 24 h.
10 mol% catalyst loading.
Detected by uncalibrated GC-MS but not isolated due to low conversion. Therefore, the exact structure is unknown.
Reaction time: 20 h.
Reaction time: 90 h.
[b]
[c]
[d]
[e]
[f]
[g]
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C H Activation by Amide Chelation Control
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of the Ru-catalyzed C O and C N activation reac- haps reflecting a steric effect. This rationalization
tions of benzamides with ArBneop derivatives estab- may also be valid for the greatly reduced yield of 2ac
lished in our previous work,[4] we screened a selection (compared with 2ab) and lack of observed couplings
of heterocyclic amides and the results are depicted in (2as and 2at) when 2,3-dimethylphenyl Bneop, mesityl
Table 1. The first heterocycle examined, the furan 3- Bneop, and 2-CF3-phenyl Bneop derivatives respec-
CONEt2 1a gave encouraging and possibly surprising tively were employed. The 4-formylphenyl Bneop
results, providing the 2-aryl product 2aa in 68% yield provided the 2-arylated product 2aq in low yield. The
by using 1.1 equiv. of PhBneop which was improved 4-chlorophenyl boronate 2ar led to inefficient cou-
to 90% yield at 1.5 equiv. of boroneopentylate stoichi- pling which may be due to a possible Ru-catalyzed
ometry (entry 1). Furthermore, application of these hydrodechlorination side reaction.[7a,9] On the other
conditions to the 4-fluorophenylBneop derivative af- hand, the 2-naphthyl Bneop derivative furnished the
forded the corresponding 2-aryl product 2aj in 92% corresponding 2-arylated product in good yield (2al),
yield. This constitutes the first example of a heterocy- suggesting successful coupling reactions of highly con-
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ꢀ
clic tertiary amide-directed ortho C H activation/ary- densed aromatics. To extend the scope of the C H
lation reaction with complete regioselectivity and coupling reaction of furan 3-CONEt2 1a, attention
high efficiency. These results encouraged the explora- was turned to screening heteroaromatic boroneopen-
tion of additional p-excessive heterocylic amides. The tylates. While efficient coupling (2an) was observed
corresponding furan 2-CONEt2 1b gave a low yield of between 1a and the 3-thiophenenylboronate, its reac-
the 3-aryl product 2b which was improved by higher tion with 2-furanyl and 2-benzofuranylboronates af-
catalyst loading (entry 2). Parallel behavior but with forded coupled products 2am and 2ao in moderate
markedly lower reactivity was observed in the thio- yields due to competitive protodeboronation as evi-
phene cases studied, whereby thiophene 3-CONEt2 1c denced by total consumption of these boronates
led to 2-arylated product 2c in 21% yield (entry 3) during the reaction.[10] Similar protodeboronation re-
while the corresponding 2-CONEt2 derivative 1d gen- sults also compromised the yields in other cases (2ae,
erated only trace amounts of the arylated product 2d 2ai–ak) when the amounts of Bneop coupling partners
(entry 4). The pyrrole N-CONEt2 1e was found also were decreased. As is commonly carried out for
to produce only a trace amount of phenylated product Suzuki–Miyaura cross-coupling reactions, increasing
2e (entry 5). Turning to the indole series, indole N- the amount of boronates to help solve this problem,
CONEt2 1f behaved similarly to the corresponding with due consideration of expense, was not attempted.
pyrrole analogue 1e in yielding only detectable Moreover, in a brief exploration of an alkyl boroneo-
amounts of product 2f (entry 6) and the 2-CONEt2 pentylate (n-BuBneop) and phenylcyclopropyl Bneop
indole derivative 1g also failed to afford the expected with the furan amide 1a, the former failed to provide
product 2g (entry 7) while, with consistency of 3-sub- product 2au while the latter gave a low yield of 2ap,
stitution (entries 1 and 3), indole-3-CONEt2 1h led to the modest success of which perhaps reflecting the
phenylated product 2h in modest yield (entry 8). N- partial sp2-character[11] of cyclopropyl carbons. Al-
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CONEt2-benzimidazole 1i also failed in the C H acti- though this is clearly an incomplete evaluation, it ap-
vation/arylation reaction (entry 9). In the p-deficient pears that alkyl boroneopentylates are not suitable
heteroaromatic amide series studied, of the three the- for the Ru-catalyzed coupling reaction.
ꢀ
oretically possible pyridine amide isomers, only the
It is noteworthy that the new Ru-catalyzed C H ac-
picolinamide 1j showed feeble reactivity to give 3-ary- tivation/arylation method of furan-3-CONEt2 for the
lated product 2j (entry 10) while the others, 1k and 1l construction of a variety of heterobiaryls (Scheme 2)
failed to undergo coupling reactions (entries 11 and complements and has the potential of superceding the
12). The pyridazine amide 1m also was found to be DoM–Suzuki cross-coupling strategy established in
mainly unreactive (entry 13).
our laboratories with the distinct advantages of non-
The screening results singled out the furan 3- requirement of cryogenic and strong base condition-
CONEt2 as an excellent substrate for the highly selec- s.[3a,b,13] To cite a very appropriate specific comparison,
ꢀ
tive C H activation/arylation reaction and therefore the lithiation–cross-coupling of 3-CONEt2 furan was
motivated its further exploration of reactivity and carried out by routes both requiring initial ꢀ788C
scope with a variety of ArBneops (Scheme 2). When DoM reactions and involving both possible combina-
ArBneops with EDGs (electron-donating groups) tions of partners, routes (a) and (b), 1a!3 and 1a!4
such as Me, CH2O-t-Bu, NMe2 and OMe were em- to afford the product 5 (Scheme 3).[13] The poor yield
ployed, products 2ab, 2ad, 2af, 2ag, 2ah were isolated of route (b) is a reflection of protodeboronation
in high yields and with exclusive C-2 regioselectively. which is problematic in Suzuki–Miyaura reactions.[14]
ꢀ
Similarly, the ArBneops containing EWGs (electron- In contrast, the new C H activation/arylation proto-
withdrawing groups) such as CF3 and F underwent ar- col affords a similar product 2ac (Scheme 2) in 50%
ylation in good yields (2ae, 2aj, 2ak) with the excep- yield. This example may be viewed as a harbinger of
ꢀ
tion of 2ai which was obtained in mediocre yield per- the future potential value of the C H activation/ary-
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Scheme 2. Ru-catalyzed cross-coupling reactions of furan-3-CONEt2 with ArBneop derivatives.
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lation method as a simple, efficient and powerful scavengers for the Ru H species in order to maintain
complement of the combined DoM–cross-coupling the catalytic cycle,[5] both the Ru H species and the
ꢀ
strategy.[3a,b]
suggested HBneop species, formed in the oxidative
Of considerable significance is that amide reduction addition and transmetalation steps, respectively, do
was not observed under the conditions of the Ru-cat- not effect reduction of the amide group. Thus, the ne-
alyzed cross-coupling reaction. This shows that, in cessity for using pinacolone (or acetone) as solvent is
ꢀ
contrast to the ketone-directed C H activation/aryla- eliminated and an alternative inexpensive solvent,
tion reaction in which pinacolone solvent or 2 equiv. most appropriately toluene, may be used.
of a ketone substrate were required to act as hydride
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C H Activation by Amide Chelation Control
Scheme 3. Two-step DoM–Suzuki cross-coupling sequence for synthesis of 2-(2-methylphenyl)-furan-3-amide.[13]
chromatography (eluent: EtOAc/hexanes) to give the prod-
uct. Caution: manipulation of reactants, catalyst and de-
gassed solvent should be performed in a glove bag.
Figure 1. Post cross-coupling chemistry of 2-aryl-3-furana-
mides.
Acknowledgements
We are grateful to NSERC Canada (Discovery Grant) for
continuing support of our synthetic programs, to Dr.
Francoise Sauriol (Queenꢀs University) for assistance in
NMR spectroscopy and to Dr. Jiaxi Wang (Queenꢀs Universi-
ty) for discussion of mass spectra.
In summary, we have (i) demonstrated the first cat-
alytic highly regioselective directed C H activation/
arylation reaction of furan tertiary amides with aryl-
ꢀ
boroneopentylates to furnish 2-aryl-3-furanamide
products; (ii) through these results, provided an effi-
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[8] a) Furan DH298(calcd.) =118 kcalmolꢀ1 (C-2-H and C-3-
H); pyrrole DH298(expt.) =112 kcalmolꢀ1 (C-2-H and C-3-
H); thiophene DH298(calcd.) =116 kcalmolꢀ1 (C-2-H) and
114 kcalmolꢀ1 (C-3-H); indole DH298(calcd.) =117 kcal
molꢀ1 (C-2-H) and 118 kcalmolꢀ1 (C-3-H); pyridine
DH298(expt.) =105 kcalmolꢀ1 (C-2-H) and 112 kcalmolꢀ1
(C-3-H and C-4-H); pyrazine DH298(expt.) =103 kcal
molꢀ1 (C-2-H). In comparison, benzene DH298(expt.)
=
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