Copper-mediated etherification of arenes with alkoxysilanes directed by an (2-aminophenyl)pyrazole group

Article abstract of DOI:10.1039/c6ra18861c

An efficient copper-mediated etherification of inert C-H bonds of (hetero)arenes with reagent-amounts of alkoxysilanes and alkanols has been developed using (2-aminophenyl)pyrazole (2-APP) as a removable directing group. The reaction is scalable, rapidly proceeds under an open atmosphere, and tolerates diverse functional groups to provide alkyl aryl ethers in high yields (up to 87%). As an application, the formal synthesis of anti-emetic drug metoclopramide is accomplished.

Full text of DOI:10.1039/c6ra18861c

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DOI: 10.1039/C6RA18861C
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Copper-Mediated Etherification of Arenes with Alkoxysilanes
Directed by (2-Aminophenyl)pyrazole Group
Received 00th January 20xx,
Accepted 00th January 20xx
Jayaraman Selvakumar, Gowri Sankar Grandhi, Harekrishna Sahoo, Mahiuddin Baidya*
DOI: 10.1039/x0xx00000x
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An efficient copper-mediated etherification of inert C–H bonds of metals.9 Consequently, a series of new reactions including
(hetero)arenes with reagent-amount of alkoxysilanes and alkanols alkoxylation have been developed (Scheme 1b). In 2013,
has been developed using (2-aminophenyl)pyrazole (2-APP) as a Daugulis and co-workers reported copper catalyzed 8-
removable directing group. The reaction is scalable, rapidly aminoquinoline (8-AQ) directed alkoxylation of benzamides.10a
proceeds under an open atmosphere, and tolerates diverse Stahl’s group also performed mechanistic studies on copper-
functional groups to provide alkyl aryl ethers in high yields (up to mediated C–H methoxylation of N-(8-quinolinyl)-benzamide in
87%). As an application, the formal synthesis of anti-emetic drug methanol.10b Recently, Shi et al. and Song et al. independently
metoclopramide is accomplished.
contributed in this field using (pyridine-2-yl)isopropyl amine
(2-PIP) and N,O-bidentate directing group (PyO) respectively.11
All of these alkoxylation processes are good; however, the
use of large excess of alkanols is essential and most often they
have been considered as the reaction solvents. This pitfall will
be more prominent in the case of precious alkanols. Moreover,
the requirements of higher reaction temperature, longer
reaction time, and expensive oxidants/additives, such as silver
salts, are also putative issues. Furthermore, the source of
alkoxy substituents has generally been paved with alcohol
substrates and search for alternative sources is
underdeveloped.12 Thus, selective installation of alkoxy
substituents for the direct synthesis of alkyl aryl ethers using
stoichiometric amount of alkoxy sources under mild reaction
conditions is highly desirable.
Transition-metal catalyzed direct functionalization of C–H bond
has emerged as a valuable tool in the contemporary organic
synthesis.1 In this regard, synthetic methodology for the
construction of C–O bond is of fundamental interest because
molecules containing this functionality are ubiquitous in
diverse natural products and functional materials.2 While
considerable progresses have been accomplished in direct
hydroxylation, acetoxylation, and phenoxylation processes,
selective installation of alkoxy substituents en route to alkyl
aryl ethers is increasingly challenging.3 This is likely because
alkanols are easily dehydrated,4 sensitive towards oxidation5
and furthermore, metal-alkoxide intermediates are prone to -
hydride elimination.6 In this scenario, success has largely been
restricted to the use of second-row transition metals and
several protocols have been established with the use of
monodentate directing groups, particularly under palladium
catalysis (Scheme 1a).7 Recently, Goo
disclosed bimetallic copper/silver
ß
en’s group also
a
catalyst for
dehydrogenative cross-coupling of 2-aryl pyridines with
alcohols at elevated temperature (140 oC).8
Since the pioneering work of Daugulis and co-workers,
removable bidentate auxiliaries have come in the limelight
owing to their unique potential for the activation of inert C–H
bonds using abundant and inexpensive first-row transition
Scheme 1. Transition-metal-catalyzed alkoxylation of C(sp2)–H bonds
Herein, we report an unprecedented method for the rapid
synthesis of alkyl aryl ethers through the copper-mediated
alkoxylation of (hetero)arenes with a range of alkoxysilanes
and alcohols in combination with hexamethyldisilane using (2-
aminophenyl)pyrazole (2-APP) as
a removable auxiliary
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Table 2. Alkoxylation of Arene C-H bond using alkoxysilanes.a
(Scheme 1c). This reaction can be performed in open-flask with
reagent-amount of alkoxide sources at moderate temperature
while obviating the need for expensive silver salts. In addition,
to demonstrate the utility of this strategy, the formal synthesis
of anti-emetic drug metoclopramide is accomplished.
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DOI: 10.1039/C6RA18861C
It is worth noting that the 2-AAP directing group is
commercially available and can also be readily synthesized in
large scale from inexpensive starting materials.13 During the
preparation of our manuscript Li’s group reported an efficient
amidation protocol using 2-APP as a directing group and
motivated us to disclose our findings on etherification of
arenes.14
We commenced our investigation with model substrate 1a
derived from 2-APP directing group (Table 1). Initially,
phenyltrimethoxysilane (2a) was selected as the source of
alkoxy functionality. Of note, unsymmetrical organosilane 2a is
well-known as aryl donor and it has been never considered in
alkoxylation reaction, conjecturing
a
distinct reaction
paradigm. After extensive screening of reaction conditions by
varying catalysts (entries 1-4), bases (entries 5-6), temperature
(entries 7-8), and solvents (entries 9-10), we were delighted to
find that the amide 1a smoothly reacted with reagent-amount
of 2a in the presence of one equivalent of Cu(OAc)2 delivering
the methoxylated product 3aa in 87% isolated yield (Table 1,
for complete optimization conditions, see the ESI, page S6).
When loading of the organosilane 2a was reduced to four and
three equivalents, the reaction yields also decreased gradually
(entries 13-14).
aReaction conditions: 1 (0.1 mmol), Cu(OAc)2 (0.1 mmol), 2 (5 equiv), K2CO3 (3
equiv), DMSO (1 mL), 80 oC, air, 3 h. Yields are isolated quantities. bFor CCDC
number, see ref 15. cReaction was conducted at 90 oC. dTBAI (0.1 mmol) was used
f
as additive. eReaction was carried out at r.t. PhSi(OEt)3 2b (5 equiv) was used.
Table 1. Optimization of the reaction conditionsa
gSi(OEt)4 2c (5 equiv) was used. hSi(OnPr)4 2d (5 equiv) was used. iSi(OnBu)4 2e (5
equiv) was used.
Effect of other directing groups has also been examined.
Consequently, the substrates containing well-known Yu’s
aminophenyloxazoline and Daugulis’s 8-aminoquinoline
directing groups were subjected to the optimized reaction
Entry Cu-Cat.
Base
K2CO3
K2CO3
Solvent Temp (oC) Yield (%)b
conditions. However, the desired methoxylated products
were obtained in moderate yields (Table 2). The amide
derived from simple aniline failed to produce the
corresponding methoxylated product . These findings disclose
4 and
1
CuCl2
DMSO
DMSO
DMSO
DMSO
DMSO
80
80
80
80
80
80
100
90
80
80
80
80
80
80
54
Trace
87
26
78
5
2
Cu(OTf)2
3
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
Cu(OAc)2 KHCO3
4c
6
5
the aptitude of 2-APP directing group for the C–H activation
strategy.
With this optimized conditions in hand, we have moved to
verify the methoxylation reaction for various substituted
amides (Table 2). The reaction is quite general. The
carboxamides with various donating substituent at p-, m-, and
o- position (3ba–3ja) generally gave high yields (57–74%). The
electron deficient amides having p-CF3, p-NO2, and m-Cl
moieties also delivered the corresponding methoxylated
products (3ka–3ma) in good yields. However, the presence of
6
Cu(OAc)2 Na2CO3 DMSO
48
7
8
9
10
11d
12e
13f
14g
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
DMSO
DMSO
DMF
50
82
46
CH3CN
DMSO
DMSO
DMSO
DMSO
0
trace
trace
78
62
aConditions: 1a (0.1 mmol), Cu(OAc)2 (0.1 mmol), PhSi(OMe)3 (2a), Base (3
equiv.), air, DMSO (1 mL), 80 oC, 3h. bYields are isolated quantities. cReaction
under N2 atmosphere. dReaction was performed with Cu(OAc)2 (30 mol%) and
oxidant Ag2CO3 (2 equiv.) under N2 atmosphere. eReaction was performed with
Cu(OAc)2 (30 mol%) and oxidant K2S2O8 (2 equiv.) under N2 atmosphere. f4
equivalents of 2a was used. g3 equivalents of 2a was used.
TBAI additive was necessary to mitigate homo-coupling by
products. The 1-naphthylamide 1n regioselectively produced
the desired compound 3na in 70% yield. The carboxamides
derived from heterocyclic compounds, such as pyridyl and
thienyl derivatives, are also suitable substrates for this
2 | J. Name., 2012, 00, 1-3
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Table 3. Cross-dehydragenative coupling of arenes and alcohols.a
reaction, delivering methoxylated products 3oa and 3pa in
67% and 50% yields respectively.
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DOI: 10.1039/C6RA18861C
The generality of the C–H methoxylation reaction with
unsymmetrical organosilane 2a prompted us to examine the
feasibility of this protocol to install the higher alkoxide
functionalities. Thus, various commercially available
unsymmetrical (2b) and symmetrical (2c–e) alkoxides were
employed (Table 2, below). Gratifyingly, under the optimized
conditions, reactions of all these alkoxysilanes uniformly
delivered the corresponding alkyl aryl ethers in high yields (64-
84%). Importantly, this methodology allows to access multi-
substituted arenes having different alkyl ether units (3db
–
3dd), for which direct synthetic protocol is still limited.
The reaction conditions of the present protocol are quite
mild; the 2-APP-directed C-H alkoxylation reaction was
achieved at 80oC. Hence, we envisaged that the
dehydrogenative coupling of Csp2–H bond and alcohols is also
feasible in the presence of a suitable silicon additive and only
use of a reagent-amount of alcohol, in contrast to the use of
alcohol as solvent, would be adequate to offer the desired
output. These will broadly extent the scope of this
methodology. Accordingly, the reaction was performed with 1
equiv. of Si2Me6 additive with methanol substrate (Table 3). To
our delight, the etherification took place with equal efficiency
delivering 3aa in 81% yield. When the reaction was performed
in the absence of Si2Me6 additive, erosion in yield was
observed (69%). This reaction conditions is also suitable for
various primary and secondary alcohols to produce aryl alkyl
ethers in high yields (Table 3). As a highlight, functionalized
aConditions: 1 (0.1 mmol), Cu(OAc)2 (0.1 mmol), R′OH (15 equiv), Si2Me6 (1 equiv),
K2CO3 (3 equiv), DMSO (1 mL), 80 oC, air, 3 h. Yields are isolated quantities.
bReaction was carried out without Si2Me6. cReaction was performed at 70 oC for 6
f
h. dAlcohol (5 equiv) was used. eFor CCDC number, see ref 15. Alcohol (2 equiv)
was used. gTBAI (0.1 mmol) additive was used
To display the synthetic utility of the present protocol, we
and sensitive alcohols such as prenyl alcohol (3bh), cinnamyl have implemented it as a key step in the formal synthesis of
alcohol (3bi), geraniol (3dj), methyl cellosolve (3bk), and anti-emetic drug metoclopramide (Scheme 2b).17 The synthesis
propargyl alcohol (3dl) gave desired products in good yields. starts from the Cbz-protected 4-amino benzoic acid. After
Substituted phenols (3bn–3bo) are also suitable reagent for installation of APP-directing group, the amide 1t was exposed
this reaction. Particularly, 4-(2-hydroxyethyl)phenol, bearing to our standard methoxylation conditions delivering the key
both phenolic and alcoholic functionality, undergoes intermediate 3ta in gram scale. Treatment of 3ta with N-
preferentially phenoxylation reaction to give 3bn in 65% yield.
Though deuterated molecules are very important in drug position. Sequential removal of 2-APP directing group and Cbz-
discovery,16 trideuteromethoxylation through direct C-H deprotection yielded the compound
(74% yield in three
chlorosuccinimide selectively delivered chlorination at the C5-
8
alkoxylation reaction remained elusive. This is likely because steps), a key precursor to synthesize metoclopramide and its
the reported methodologies generally demand solvent level of family of 5-HT4 receptor agonists.17b
expensive deuterated alcohols. In this scenario, our approach
In order to probe the alkoxylation mechanism, a series of
is highly rewarding. Using reagent amount of methanol-d4 control experiments have been conducted. The methoxylation
under our standard conditions, trideuteromethoxylated reactions using 2a and methanol were completely arrested in
product 3bp was obtained in 78% yield. The the presence of radical scavengers such as TEMPO and BHT,
deuteromethoxylation reaction was also successfully extended suggesting the involvement of a radical species in the reaction
to the trifluoromethyl and styryl-substituted amides and pathway (Scheme 3a). When the methoxylation reaction was
heterocyclic amide to generate 3kp
,
3qp and 3op in 71, 77, performed with an equal mixture of 2a with 1b and d5-1b
and 69% yields respectively.
respectively under standard reaction conditions for 1h, a
Of note, the 2-APP directed alkoxylation protocol is also moderate kinetic isotope effect of kH/kD = 2.5 was observed
efficient with alkene substrates, showcasing -alkoxy (Scheme 3b). In case of methanol, the kinetic isotope effect
substituted tiglic (3ra and 3rp) and methacrylic (3sa) amides was much prominent (kH/kD = 5.1). Further, when the reaction
with good yields.
was performed with methanol-d4, no deuterium incorporation

Pleasingly, the directing group can be easily be removed by was detected in the recovery starting material (Scheme 3c).
Lewis acid mediated methanolysis of the amide bond, resulting These cumulative results suggest that the 2-APP-directing
alkyl aryl ether
7 in 90% yield with the recovery of 2-APP group assisted C–H bond cleavage is irreversible and possibly
directing group in 77% yield (Scheme 2a).
involved in the rate determining step.
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substrates scope with respect to both arenes and alkoxide
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sources, and also suitable to prepare deuDteOrIa: 1t0e.d10m39o/Cle6cRuAl1e8s8.6A1Cs
an application of this methodology, we have presented a
formal synthesis of anti-emetic drug metoclopramide.
Mechanistic studies demonstrated an involvement of radical
pathway. The further effectiveness of the 2-APP directing
group for various C–H bond functionalizations and detailed
mechanistic studies are underway.
We gratefully acknowledge CSIR New Delhi for the financial
support (02(0212)/14/EMR-II). G.S.G. acknowledges UGC New
Delhi for a JRF and H. S. acknowledges IIT-Madras for HTRA.
Scheme 2. (a) Removal of the 2-APP directing group and (b) formal synthesis of
anti-emetic drug metoclopramide via C–H activation.
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Although mechanistic details must await further
investigation, based on preceding discussion a plausible
reaction mechanism was depicted in Scheme 4. After
complexation of
species is formed via base-assisted C–H bond cleavage.
Single electron oxidation promoted by copper acetate
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product
1 with copper catalyst, Cu(II)cyclometalated
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ß
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Table of Content
(2-Aminophenyl)pyrazole directed copper mediated C–H etherification of (hetero)arenes is described.