Rh(III)-Catalyzed Redox-Neutral Unsymmetrical C-H Alkylation and Amidation Reactions of N-Phenoxyacetamides

Article abstract of DOI:10.1021/jacs.7b10349

A Rh(III)-catalyzed unsymmetrical C-H alkylation and amidation of N-phenoxyacetamides with diazo compounds has been developed under mild and redox-neutral conditions, producing dinitrogen as the only byproduct. The reaction represents the first example of one-step, unsymmetrical difunctionalization of two ortho-C-H bonds. Experimental and computational studies support that N-phenoxyacetamides most likely undergo an initial ortho-C-H alkylation with diazo compounds via a Rh(III)-catalyzed C-H activation, and the resulting Rh(III) intermediate subsequently undergoes an intramolecular oxidative addition into the O-N bond to form a Rh(V) nitrenoid species that is protonated and further directed toward electrophilic addition to the second ortho position of the phenyl ring. This work might provide a new direction for unsymmetrical C-H difunctionalization reactions in an efficient manner.

Full text of DOI:10.1021/jacs.7b10349

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Communication
Rh(III)-catalyzed Redox-Neutral Unsymmetrical C-H
Alkylation and Amidation Reactions of N-Phenoxyacetamides
Yunxiang Wu, Zhaoqiang Chen, Yaxi Yang, Weiliang Zhu, and Bing Zhou
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 17 Nov 2017
Downloaded from http://pubs.acs.org on November 17, 2017
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Amidation Reactions of N-Phenoxyacetamides
Yunxiang Wu,a,b,‡Zhaoqiang Chen,c,‡ Yaxi Yang,a,b Weiliang Zhu,*,c Bing Zhou*,a,b
aDepartment of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
bUniversity of Chinese Academy of Sciences, Beijing 100049, China
cDrug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Supporting Information Placeholder
(a) mono ortho C-H functionalization
ABSTRACT: A Rh(III)-catalyzed unsymmetrical C-H alkyla-
cat. M
DG
DG
well explored
''A''
one-step
tion and amidation of N-phenoxyacetamides with diazo
compounds has been developed under mild and redox-
neutral conditions, producing dinitrogen as the only by-
product. The reaction represents the first example of one-
step, unsymmetrical difunctionalization of two ortho C-H
bonds. Experimental and computational studies support that
N-phenoxyacetamides most likely undergo an initial ortho C-
H alkylation with diazo compounds via a Rh(III)-catalyzed C-
H activation, and the resulting Rh(III) intermediate subse-
quently undergo an intramolecular oxidative addition into
the O−N bond to form a Rh(V) nitrenoid species that is pro-
tonated and further directed toward electrophilic addition to
the second ortho position of the phenyl ring. This work
might provide a new direction for unsymmetrical C-H di-
functionalization reaction in an efficient manner.
A
H
DG = directing groups
(b) double ortho C-H functionalization
H
A
cat. M
DG
limited to installation of the same two substituents
often nonselective and/or uncontrollable
mixture of mono- and di-funcationalization
DG
''A''
one-step
H
A
(c) one-step unsymmetric C-H difunctionalization with the simultaneous introduction of two different substituents
B
H
cat. M
DG
DG
H
no example
''A'' + ''B''
one-step
A
In recent years, transition-metal-catalyzed C-H functional-
ization assisted by an oxidizing directing group (N-O or N-N
DGs) has been emerged as a redox-economic and waste-
reducing strategy in the formation of C-C bonds (Scheme
2a).6,7 In this strategy, the oxidizing directing group also acts
as an internal oxidant by the cleavage of an oxidizing bond
(X−Y), with the liberation of the cleaved unit “Y”.8 On the
other hand, the oxidizing directing group can undergo an
intramolecular migration of the unit “Y” to the ortho postion
of the phenyl ring in the presence of large excess of strong
acids9 or via a Ir- or Rh-catalyzed C-H activation strategy
developed by Zhao and Glorius very recently (Scheme 2b).10
However, these two areas were developed separately and
there has been no report which combines ortho C-H func-
tionalization and an intramolecular migration of the cleaved
unit from the oxidizing directing group to the arene simulta-
neously, thus leading to the realization of a one-step, un-
symmetrical C-H difunctionalization of arenes.
The transition-metal-catalyzed directed functionalization
of C(sp2)-H bonds has emerged as a powerful and straight-
forward tool for the synthesis of various structurally diverse
organic molecules from less less-functionalized substrates in
the past decades.1 While ortho mono-C-H functionalization
of arene with various coupling partners is efficiently accom-
plished by chelation-assisted metalation (Scheme 1a),1 double
C-H functionalization is often nonselective and/or uncon-
trollable and largely limited to introduction of the same two
coupling partners (Scheme 1b).2,3 Usually, additional steps,
and/or different catalytic systems, and/or different reaction
conditions are required for the second ortho C-H functional-
ization to install another different functional group.4 There-
fore, catalytic, one-step, unsymmetrical C-H difunctionaliza-
tion with the simultaneous introduction of two different
substituents under the single reaction condition is highly
desirable (Scheme 1c).5
Scheme 2.Redox-neutral C-H activationassisted by an
oxidizing directing group
Scheme 1. Transition-metal-catalyzed C-H mono- or
di-functionalization
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O
In this context, we wondered whether a Rh(III)-catalyzed
O
HN
R2
3
4
5
6
7
8
9
ortho unsymmetrical C-H difunctionalization of N-
phenoxyacetamides is possible by choosing appropriate cou-
pling partner and reaction condition provided that the acet-
amide group could function as a cleavable directing group to
facilitate the ortho C−H fuctionaliztion, and also an essential
coupling partner for the second ortho C−H amidation via an
intramolecular migration strategy. With our continuing in-
terest in the Rh(III)-catalyzed C-H functionalization with
diazo compounds,11 we herein report the first Cp*Rh(III)-
catalyzed, one-step, mild, redox-neutral ortho unsymmetrical
C-H alkylation and amidation of N-phenoxyacetamides via a
ortho C-H alkylation with diazo compounds and subsequent
intramolecular amide transfer strategy (Scheme 2c).
(Cp*RhCl2)2 (2.5 mol %)
CsOAc (10 mol %)
O
N2
OH
N
R2
R1
H
R1
R3
R3
R3
DCE, 40 oC, 12 h
R3
1
2
3
O
O
O
O
O
HN
Bn
HN
i-Pr
OH
HN
HN
Me
OH
HN
Et
OH
OH
COOMe
OH
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
3d, 81%
3b, 92%
3a, 87%
3c, 76%
3e, 82%
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O
O
O
Ts
HN
Me
OH
HN
Me
OH
HN
HN
Me
OH
OH
COOMe
COOMe
COOMe
COOMe
Ph
COOMe
COOMe
MeOOC
3i, 83%
COOMe
3h, 76%
COOMe
3g, 85%
3f, N.R.
We initiated our studies with the investigation of the Rh-,
Ir-, Ru-, Co-catalyzed unsymmetrical ortho C-H difunctional-
ization of N-phenoxyacetamide (1a) with various coupling
partners such as alkynes, alkenes and diazo compounds. To
our delight, when treating 1a with diazomalonate (2a)in the
presence of (Cp*RhCl2)2 (2.5 mol %) and AgSbF6 (10 mol %)
in DCE at room temperature for 12 h, the desired unsymmet-
rical ortho C-H alkylation and amidation product 3a was
obtained in 8% yield (Table S1 in the Supporting Infor-
mation, entry 1). Encouraged by this result, other additives
were next screened. An addition of acid completely inhibited
the reaction (entry 2) and gratifyingly, replacement the addi-
tive AgSbF6 with CsOAc (10 mol %) significantly improved
the yield to 74% (entry 3). When Ir(III), Co(III) and Ru(II)
catalysts were employed, the desired reaction did not occur
(entries 4-6). A screening of solvents indicated that toluene
and 1,4-dioxane provided inferior results (entries 7-8). MeOH
gave the mono C-H alkylation product in agreement with
previous report8j and no any desired C-H difunctionalization
product 3a was observed, indicating that protic solvent is
adverse to intramolecular amide transfer (entry 9). Control
experiments revealed that Cp*Rh(III) catalyst is necessary for
this transformation (entry 10). Finally, we were pleased to
find that the product 3a could be obtained in 87% yield by
O
O
O
O
HN
Me
OH
HN
Me
OH
HN
Me
OH
HN
Me
OH
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
Cl
NC
F
F3
C
COOMe
COOMe
3j, 72%
3m, 82%
3k, 83%
3l, 85%
O
O
O
HN
Me
OH
HN
Me
OH
HN
Me
OH
Me
Cl
COOMe
COOMe
COOMe
COOMe
COOMe
Br
COOMe
3o, 87%
3p, 85%
3n, 82%
Large steric
hindrance
HN
O
O
O
O
O
HN
Me
OH
HN
Me
OH
Me
OH
HN
Me
OH
HN
Me
OH
Me
Me
COOBn
COOEt
COOMe
COOiPr
COOMe
COOMe
COOBn
3u, 81%
COOEt
3s, 92%
COOMe
3r, 78%
COOiPr
3t, 87%
3q, 78%
aReaction conditions: Reactions were carried out by using
(RhCp*Cl2)2 (2.5 mol%), CsOAc (10 mol%), 1 (0.2 mmol) and
o
2 (0.24 mmol) in a DCE (2 mL) at 40 C for 12 h; lsolated
yield.
More significantly, for meta-substituted and meta, para-
disubstituted substrates, the C-H alkylation with diazo com-
pounds showed excellent regioselectivity in favor of the steri-
cally more accessible C-H bond, and the subsequent C-H
amidation could also take place smoothly, despite the large
steric hindrance of the second C-H bond,delivering 1,2,3,4-
tetrasubstituted and 1,2,3,4,5-pentasubstituted benzene de-
rivatives 3o-3r in 78-87% yield. In particular, the meta-
isopropyl-substituted derivative is also a productive substrate
(3r), thus indicating a high steric tolerance of this system.
Various α-diazomalonates (3s-u) were investigated under the
optimized condition and coupled smoothly in 81-92% yields.
When diazoacetoacetate was used, no desired product was
obtained, suggesting that the electron nature of diazo sub-
strates is important for this C-H alkylation and subsequent
amidation process.
o
slightly increasing the reaction temperature to 40 C (entry
11).
With the optimized reaction conditions in hand, we em-
barked on an investigation of the scope of the unsymmetrical
C-H alkylation and amidation reaction (Scheme 3). N-
Phenoxyamides with acetyl, propionyl, isobutyryl, cyclo-
propylcarbonyl, and phenylacetyl substituents on nitrogen
gave the corresponding products 3a-e in 76-92% yields.
However, no product was obtained with a N-Ts group. Signif-
icantly, electron-rich (3g) and electron-withdrawing (3i-n)
substituents at the para positions all afforded good yields. To
our delight, the functional groups such as ester (3i), nitrile
(3j) and halogen (3m and 3n) were all nicely tolerated, ena-
bling further functionalization. The structure of 3n was un-
ambiguously confirmed by an X-ray crystallographic analysis
(CCDC 1573557).
Phenols are ubiquitous in many natural products, pharma-
ceuticals, biologically active compounds, and they are also
used as important intermediates in synthetic organic chemis-
try.12 One-step, unsymmetrical twofold ortho C−H function-
alization in these bioactive skeletons could provide a power-
ful tool in the chemical synthesis of functionalized ana-
logues. The utility of this unsymmetrical C−H alkylation and
amidation reaction as a tool for late-stage modification of
bioactive complex estrone derivative 4 was demonstrated,
Scheme 3. Substrate Scopea
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providing the alkylation and amidation product 5 in 81%
served, indicating that the ortho amidation takes place in-
tramolecularly (Scheme 5a). The reaction of 2-
acetamidophenol with dizaomalonate 2a did not deliver the
product 3a and the reaction of N-(o-tolyloxy)acetamide 1v in
the presence or absence of 2a did not give 3v (Scheme 5b),
ruling out the pathway involving an initial intramolecular
amidation transfer and subsequent phenol-directed C-H
alkylation with diazo compounds. Furthermore, we prepared
a rhodacycle A,8a,8l which successfully catalyzed the current
C-H alkylation and amidation reaction, suggesting that com-
plex A is most likely involved in the catalytic cycle (Scheme
5c). A KIE of 4.2 was observed in a competitive experiment
(Scheme 5d). Moreover, a kinetic isotopic effect (KIE) of 2.3
was observed from two side-by-side reactions using 1a and
1a-d5 (Scheme 5d). Both results indicated that the C(sp2)-H
bond cleavage might be related to the rate-limiting step.13
Addition of TEMPO or BHT had a negligible effect on the
reaction, suggesting that the C-H alkylation and amidation
reaction is not likely involved in a radical pathway (Scheme
5e). The competitive reaction of an equimolar amount of 1g,
1k, and 2a under the standard conditions provided a mixture
of 3g and 3k in a 7:3 ratio, indicating that the electron-rich
arenes inherently react preferentially (Scheme 5f).
yield and exhibiting excellent site-selectivity (Scheme 4a).
Moreover, dopamine derivative 7 was successfully obtained
in excellent yields, highlighting the method’s mild conditions
and excellent functional group tolerance (Scheme 4b). To
further highlight the synthetic utility of the reaction devel-
oped herein, treatment of 3a under acidic reaction condition
provides benzoxazole 8a in 79% yield which can further un-
dergo a decarbonylation to deliver 7-benzoxazoleacetic acid
9a in 83% yield (Scheme 4c). In addition, treatment of 3a
with LiOH resulted in decarbonylation and esterification to
afford bioactive 7-amino-2(3H)-benzofuranone 10a in good
yield (Scheme 4d).
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Scheme 4.The synthetic application of the C-H alkyl-
ation and amidation reaction.
On the basis of these preliminary studies, we propose the
catalytic cycle involving an initial C-H activation to form
rhodacycle A (Scheme 6). Coordination of the diazo sub-
strate 2a to A and a subsequent intramolecular 1,2-migratory
insertion of the aryl group provides the intermediate B with
extrusion of N2. In path a, an oxidative addition of Rh(III)
into the N-O bond gives the five-membered Rh(V) nitrenoid
C14and subsequent protonation of C affords the intermediate
D. In addition, D can also be formed by a protonation of B
and subsequent intramolecular oxidative addition of Rh into
the N-O bond (path b). An intramolecular electrophilic
nitrenoid addition gives the intermediate E which undergoes
a protonation with HOAc and subsequent isomerization to
release product 3a and regenerate the active catalyst.
Scheme 5. Experimental Mechanistic Studies
Scheme 6.Proposed Mechanism.
To gain further insights into this unprecedented unsym-
metrical C-H alkylation and amidation reactions, including
the distinction between pathway a and pathway b, DFT cal-
culations were performed with Gaussian 09 (Figure 1).15 First,
the coordination of the diazo substrate to rhodacycle A and
subsequent denitrogenation forms intermediate A-1 which
undergoes a Rh−aryl migratory insertion to give B with an
overall 28.3 kcal/mol exothermicity. In path a, an intramo-
lecular oxidative addition of Rh into the O−N bond occurs
To understand the mechanism of the C-H alkylation and
amidation reaction, the crossover experiment using equally
reactive substrates 1c and 1k was first carried out under the
standard conditions. The reaction of the mixture gave only
products 3c and 3k and no any crossover products were ob-
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via TS1 with anactivation energy barrier of 17.9 kcal/mol,
ACKNOWLEDGMENT
forming Rh(V) nitrenoid species C.14Protonation of C by
HOAc provides acyclic intermediate D with 9.3 kcal/mol
endothermicity and subsequent nitrenoid addition to the
second ortho carbon has a low barrier of 5.7 kcal/mol (TS2),
producing a dearomatized intermediate E. Finally, Proto-
nolysis of E with HOAc and subsequent aromatization gen-
erates 3a and regenerates the active catalyst Cp*Rh(OAc)2
with 35.8 kcal/mol exothermicity. In pathway b, intermediate
B undergoes a protonation first to give F with 11.6 kcal/mol
endothermicity and subsequent oxidative addition of Rh(III)
into the O−N bond has a high barrier of 32.5 kcal/mol (TS3),
which is clearly disfavored in comparison to pathway a.
“1000-Youth Talents Plan” and the CAS Pioneer Hundred
Talents Program is gratefully acknowledged.
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Figure 1.Energy profiles and geometry information for the C-
H alkylation and amidation reactions.
In summary, we have developed an unprecedented
Cp*Rh(III)-catalyzed unsymmetrical C-H alkylation and
amidation reaction of N-phenoxyacetamides with diazo
compounds under mild and redox-neutral conditions, giving
N2 as the sole by-product. Through experimental and compu-
tational studies, we elucidated that an initial Rh(III)-
catalyzed ortho C-H alkylation of N-phenoxyacetamides with
diazo compounds occurs first and the resulting Rh(III) in-
termediate subsequently undergo an intramolecular oxida-
tive addition into the O−N bond, forming a Rh(V) nitrenoid
species that is protonated by HOAc and subsequently further
directed toward electrophilic addition to the second ortho
position of the phenyl ring. The unprecedented one-step,
unsymmetrical C-H difunctionalization of phenol derivatives
shows potential applications in the late-stage diversification
of natural products. This work might provide a new direction
for unsymmetrical C-H difunctionalization reaction in an
efficient manner.
ASSOCIATED CONTENT
Supporting Information
Detailed experimental procedures, characterization data,
andDFT data. This material is available free of charge via
theInternet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
E-mail (B.Z.): zhoubing2012@hotmail.com;
zhoubing@simm.ac.cn;E-mail (W.Z.): wlzhu@mail.shcnc.ac.cn;
Author Contributions
‡These authors contributed equally.
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