Ruthenium(0)-Catalyzed C-H Arylation of Aromatic Imines under Neutral Conditions: Access to Biaryl Aldehydes

Article abstract of DOI:10.1021/acs.orglett.6b01738

The first ruthenium(0)-catalyzed C-H bond arylation of aromatic imines with arylboronates under neutral conditions is reported. This versatile method provides rapid access to a wide range of biaryl aldehydes that are difficult to assemble using traditional methods with high atom economy. A new hydrogen acceptor for Ru(0) arylation has been identified. This atom-economical strategy has potential for an array of direct applications in Ru(0)-catalyzed C-H bond arylations using removable directing groups. An indole synthesis by a sequential one-pot, multiple C-H activation protocol is reported.

Full text of DOI:10.1021/acs.orglett.6b01738

Letter
pubs.acs.org/OrgLett
Ruthenium(0)-Catalyzed C−H Arylation of Aromatic Imines under
Neutral Conditions: Access to Biaryl Aldehydes
Feng Hu and Michal Szostak*
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
S
* Supporting Information
ABSTRACT: The first ruthenium(0)-catalyzed C−H bond
arylation of aromatic imines with arylboronates under neutral
conditions is reported. This versatile method provides rapid
access to a wide range of biaryl aldehydes that are difficult to
assemble using traditional methods with high atom economy.
A new hydrogen acceptor for Ru(0) arylation has been
identified. This atom-economical strategy has potential for an
array of direct applications in Ru(0)-catalyzed C−H bond
arylations using removable directing groups. An indole
synthesis by a sequential one-pot, multiple C−H activation protocol is reported.
n the past decade, selective C−H functionalization has
revolutionized the field of organic synthesis; however,
arylation using imines as versatile aldehyde equivalents is
I
challenging for several reasons: (i) an efficient acceptor for the
Ru−H species must be found that would be accommodated
under the reaction conditions;12 (ii) the imine can undergo
competing reduction with Ru−H species;13 (iii) the imine
should be stable under the reaction conditions to prevent
formation of Ru-amine complexes;14 (iv) the imine should be
electronically balanced to facilitate Ru coordination/C−H
activation steps under mild conditions.14 Finally, the formation
of dialkoxyborane, a poison for Ru(0), must be avoided.5
Within our program on metal catalysis,15 herein, we report the
first Ru(0)-catalyzed C−H bond arylation of aromatic imines
with arylboronates (Figure 1).7−9 This atom-economical Ru(0)-
catalyzed C−H activation/cross-coupling has two major
advantages: (i) in a Ru(0)/Ru(II) cycle, inorganic oxidant and
base are not required, leading to an inorganic waste-minimized
protocol;1−3 (ii) rationally designed, hemilabile, carbonyl-based
directing groups16 modulate the selectivity of C−H cross-
coupling under thermodynamic C−H cleavage4 that can be
applied to a wide range of available carbonyl substrates.
Moreover, we demonstrate that ketimines provide an unprece-
dented controlling factor for highly selective Ru(0)-catalyzed
monoarylation;17 note that Ru(0)-catalyzed, ketone-directed
arylation is limited to sterically hindered ketones to prevent
diarylation.5 The functional-group-tolerant Ru3(CO)12 catalyst
delivers the products in high yields and with broader
compatibility than RuH2(CO)(PPh3)3.5,6 We have identified a
new hydride acceptor that may find applications beyond this
work.18 Our strategy holds a potential for direct applications in
Ru(0)-catalyzed C−H bond functionalization using removable
directing groups.
significant challenges in the synthesis of common building
blocks using practical, atom-economical conditions still remain.1
Recently, notable progress has been achieved in the development
of ruthenium-catalyzed C−H functionalization fueled by the
economic advantages of ruthenium.2 In this context, the majority
of recent advances focused on versatile Ru(II) catalysts.2a
However, the development of robust methods using this catalytic
manifold might be complicated by less favorable atom economy.3
An alternative strategy involving C−H activation by a Ru(0)/
Ru(II) cycle offers several advantages, including (i) operationally
simple conditions, (ii) C−H activation in the absence of
inorganic oxidants and/or bases, and (iii) mild neutral conditions
for C−H functionalization.4 Ru(0)-catalyzed C−H arylation of
aromatic ketones was achieved using a RuH2(CO)(PPh3)3
catalyst and pinacolone as a hydrogen acceptor; however, this
method is limited to sterically hindered ketones to prevent
diarylation.5 Moreover, other carbonyl groups such as esters and
ketones are incompatible with the RuH2(CO)(PPh3)3 catalyst.4,5
Recently, Snieckus significantly extended this activation manifold
by employing amides as the regioselectivity controlling directing
group.6 Due to the amide bond planarity, only a single isomer
was observed in a range of C−X (X = N, O) activation reactions.
Unfortunately, the amide-directed C−H activation was reported
to occur only with electron-rich heterocycles.6a
While direct ortho-arylation of aromatic aldehydes is currently
beyond the scope of C−H activation manifolds due to weak
coordination and low stability under the conditions required for
C−H activation, we hypothesized that the atom-economical
Ru(0)-catalyzed C−H arylation7 directed by imines8,9 as
versatile aldehyde equivalents10,11 could provide a general
route to nitrogen-containing biaryls as well as to functionalized
biaryl aldehydes that are high-value motifs in pharmaceuticals10
and could serve as powerful synthetic linchpins.11 The
development of a broadly applicable Ru(0)-catalyzed C−H
Received: June 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01738
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Organic Letters
Letter
a
Table 1. Ru(0)-Catalyzed C−H Arylation of Imines
b
entry
catalyst
acceptor
BA
solvent
yield (%)
1
2
RuH2(CO)(PPh3)3
RuH2(PPh3)4
RhCl(PPh3) 3
[Rh(COD)Cl]2
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
toluene
toluene
toluene
toluene
toluene
acetone
dioxane
pinacolone
i-PrOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
8
11
9
BA
3
BA
4
BA
6
5
BA
98
57
82
91
33
74
64
55
<2
5
6
BA
7
BA
8
BA
9
BA
10
11
12
13
styrene
norbornene
dec-1-ene
acrylonitrile
BA
c
14
d
15
BA
61
80
93
90
88
e
16
BA
f
17
BA
g
18
BA
Figure 1. (A) Ru(0)-catalyzed C−H arylation of ketones and amides
using RuH2(CO)(PPh3)3. (B) This work: functional-group-tolerant
Ru(0)-catalyzed C−H arylation of imines as synthetic aldehyde
equivalents using Ru3(CO)12. (C) Biaryl aldehyde linchpins.
h
19
BA
a
Imine (0.20 mmol), PhBnep (1.5 equiv), acceptor (2 equiv), catalyst
b
1
(5 mol %), solvent (1.0 M), 125 °C, 15 h. Determined by H NMR
and GC. PPh3 (5 mol %). N-Me instead of N-Ph. N-t-Bu. N-2,6-
Me2C6H3. PhBnep (1.0 equiv). PhBpin (1.5 equiv). BA =
benzylideneacetone. Bnep = 5,5-dimethyl-1,3,2-dioxaborolane.
c
d
e
f
g
h
We started by studying the coupling of various imines of o-
tolualdehyde with phenylboronate esters in the presence of
Ru(0) catalysts and hydride acceptors. Selected results are
outlined in Table 1. Complex mixtures were formed in absence of
the acceptor. After extensive optimization, we found that the
proposed arylation is indeed feasible in the presence of
Ru3(CO)12 catalyst, benzylideneacetone (BA) as Ru−H accept-
or, N-aryl imine (1) as C−H functionalization substrate, and
neopentyl aryl boronate (2), providing the desired C−H
arylation product in excellent 98% yield with no observable
side reactions (entries 1−19). RuH2(CO)(PPh3)3 employed for
ketone arylation5 and various Rh(I) and Ru(II) conditions (not
shown) failed to provide the desired product. The nature of Ru−
H acceptor is critical, with strained and aromatic olefins
providing inferior results (entries 6−13). Coordination of the
carbonyl to Ru might facilitate hydride transfer.19 Phosphine
ligands had a deleterious effect (entry 14). Other imines (entries
15−17), organometallic reagents, and conditions tested (entries
18−19) afforded the product in lower yields.
Scheme 1. Ru(0)-Catalyzed C−H Arylation: Scope of
Nucleophiles
ab
,
Next, the preparative scope was evaluated (Scheme 1). All C−
H arylation products were obtained directly as aldehydes after
mild hydrolysis.11 Aryl boronates containing electron-rich (3b,c)
and electron-poor (3d) functional groups afforded the desired
products in excellent yields. Electrophilic functional groups, such
as p-fluoro- (3e), p-chloro- (3f), p-ester (3g), p-ketone (3h), and
p-olefin (3i), are perfectly accommodated. Reductive dechlori-
nation was not observed under the reaction conditions,6a albeit
the product was obtained in lower yield due to low conversion.
Highly electron-donating (3j) and electron-withdrawing sub-
stituents (3k), polyarenes (3l), and electrophilic heterocycles
(3m−3o) are well-tolerated. The protocol could be extended to
vinyl (3p) and even alkyl nucleophiles (3q) under the standard
conditions. Of note is the facility with which ketone and ester-
containing nucleophiles can be employed, outperforming the
a
Imine (0.20 mmol), PhBnep (0.30 mmol), BA (0.24 mmol), catalyst
b
(5 mol %), PhMe (1.0 M), 125 °C, 1−15 h. All yields are isolated
yields of the corresponding aldehyde after hydrolysis. See SI for details.
RuH2(CO)(PPh3)3-catalyzed protocol.5,6 Evaluation of addi-
tional functional group tolerance is currently underway.
B
DOI: 10.1021/acs.orglett.6b01738
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Organic Letters
Letter
This new Ru(0)-catalyzed method enables access to a broad
range of aldehydes with unconventional selectivity (Scheme 2).
First, significant steric and electronic effects of substituents are
observed (3r−3x). Ortho-substituted imines were found to be
excellent substrates (3r−3t).
Scheme 3. In Situ Aldehyde Arylation
Scheme 4. Gram Scale Synthesis
Scheme 2. Ru(0)-Catalyzed C−H Arylation: Scope of
a,b
Imines
consistent with reductive elimination via a migration π−π
coupling mechanism.4 (2) Experiments with electronically
diverse boronates revealed that the electronic nature of the
nucleophile does not significantly affect the yield, consistent with
the nitrogen-assisted B−Ru transmetalation.20 (3) Quantitative
reduction of BA to 4-phenylbutan-2-one is observed.18,19 (4)
Electronic effects in the mono/diarylation selectivity of meta-
substituted imines (3v,w) are consistent with imine coordination
to the Ru center during the cycle. We have not detected products
resulting from carbonyl reduction in the acceptor.19 Likewise, the
formation of dialkoxyborane was not observed.21 Further studies
to elucidate the mechanism are ongoing.
We demonstrated the utility of products in the synthesis of a
diverse set of building blocks (Scheme 5). The in situ Ru(0)-
a
Scheme 5. Product Transformations
a,b
c
See Scheme 1. ArBnep (1−3 equiv). Ketimine substrate.
Excellent regioselectivity was observed in the arylation of
electron-poor meta-substituted imines (3v, >50:1). Electron-rich
substituents resulted in double arylation (3w). This reactivity is
complementary to the monoarylation under Pd(II)/(0)
catalysis.8a A plot of log(meta‑selectivity) versus σ* gives Hammett
correlation (ρ = 1.37; R2 = 0.93), indicating that electronic effects
determine the reaction outcome. While the unsubstituted imine
substrate afforded the valuable diarylated aldehyde (3y), the
corresponding ketimine enabled high regiocontrol (3z, >12:1).17
This reactivity represents a significant bonus compared to Ru(0)-
catalyzed ketone-directed arylation, in which steric hindrance
(e.g., t-Bu) was required to prevent diarylation.5 Heteroatom-
containing imines (3aa,3ab) and polyarenes (3ac) are well-
tolerated. Arylation via a six-membered metalacycle was not
observed (3y). The reaction also tolerates removable alcohol
protecting groups (3ad). Furthermore, vinyl groups undergo sp2-
arylation (3ae).
a
Reagents and conditions: (a) NaClO2, MeCN, H2O, rt, 18 h, 76%;
(b) NaBH4, p-TsOH, EtOH, rt, 2 h, 81%; (c) n-BuLi, THF, 78 °C to
rt, 2 h, 85%; (d) NaBPh4, [RhCl(cod)]2, xylenes, 160 °C, 24 h, 70%;
(e) HCl, Et2O, rt, 3 h, quant.
Importantly, due to the mild, waste-minimized conditions, the
reaction sequence can be readily performed by starting directly
from aldehyde by an in situ imine synthesis/post-C−H arylation
hydrolysis (Scheme 3). We determined that the method for an in
situ arylation is general and preferred when less stable imines are
used.
The C−H arylation was carried out on a gram scale,
demonstrating scalability of our protocol (Scheme 4).
Studies were performed to gain preliminary insight into the
reaction mechanism (see SI). (1) Intermolecular competition
experiments between differently substituted imines revealed that
electron-deficient substrates are inherently more reactive,
catalyzed C−H arylation/Pd(II)-catalyzed indole synthesis
underscores the potential of our mild protocol in the synthesis
of biologically active heterocycles via multiple C−H function-
alizations.22
In conclusion, we have reported the first Ru(0)-catalyzed C−
H arylation of aromatic imines with organoboranes under neutral
conditions. This strategy provides rapid access to functionalized
biaryl aldehydes that are important building blocks in organic
synthesis. We expect that this method will lead to the
C
DOI: 10.1021/acs.orglett.6b01738
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Ru(0) catalysts.
ASSOCIATED CONTENT
■
S
* Supporting Information
(7) Review on C−H arylation with organometallics: Giri, R.; Thapa, S.;
Kafle, A. Adv. Synth. Catal. 2014, 356, 1395.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01738.
(8) Literature precedents for imine-directed C−H arylation processes
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D. G.; Wang, Y.; Shi, Z. J. Org. Lett. 2010, 12, 184. Pd(II)/(IV):
(f) Neufeldt, S. R.; Sanford, M. S. Adv. Synth. Catal. 2012, 354, 3517.
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Procedures and analytical data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: michal.szostak@rutgers.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by Rutgers University. The
Bruker 500 MHz spectrometer used in this study was supported
by the NSF-MRI grant (CHE-1229030). M.S. thanks ORAU for
the Ralph E. Powe Junior Faculty Enhancement Award.
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