Bulky Phosphane Ligand for Monoselective Ruthenium-Catalyzed, Directed o -C-H Arylation with Challenging Aryl Chlorides

Article abstract of DOI:10.1055/s-0036-1588635

Functionalized aryl chlorides are more economically attractive but usually much more difficult as substrates in metal-mediated couplings than the corresponding bromides and iodides. A catalyst prepared from a bulky (biaryl)diphenyl phosphane and a common ruthenium source (1:1) mediates selective direct monoarylations of arenes bearing 2-pyridyl and related ortho-directing groups in good yields. Sequential arylations to heterodiarylated products also proceed in satisfactory yields.

Full text of DOI:10.1055/s-0036-1588635

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
Y.-G. Li et al.
Letter
Synlett
Bulky Phosphane Ligand for Monoselective Ruthenium-Catalyzed,
Directed o-C–H Arylation with Challenging Aryl Chlorides
You-Gui Lia
Zhen-Yu Wanga
Ya-Ling Zoua
Chau-Ming Sob
Fuk-Yee Kwong*b
Hua-Li Qinc
Bn
N
O
Ru cat.
(2–5 mol%)
DG
DG
N
Ar
Cl
+
K2CO3, NMP
120–140 °C
Ar
N
H
S
76%
N
Cat.:
Ph2P
55%
N
Me
N
Eric Assen B. Kantchev*a
N
N
S
N
N
a School of Chemistry and Chemical Engineering, Hefei University
of Technology, 193 Tunxi Road, Hefei, 230009, P. R. of China
ekantchev@hfut.edu.cn
66%
NH2
Me
N
CN
Me
+
61%
Me
80%
NH
F
[RuCl2(p-cymene)]2
78%
ekantchev@gmail.com
b Department of Applied Biology and Chemical Technology, Hong
Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
SAR, P. R. of China
fuk-yee.kwong@polyu.edu.hk
c School of Chemistry, Chemical Engineering and Life Science,
Wuhan University of Technology, 205 Luoshi Road, Wuhan,
430070, P. R. of China
Received: 23.08.2016
Accepted after revision: 05.10.2016
Published online: 09.11.2016
and useful biarylphosphane ligands have been made com-
mercially available (Figure 1). This should greatly facilitate
their use in other metal-catalyzed reactions, where they
could be expected to bring similar enhancements in cata-
lytic activity and selectivity observed in cross-couplings.
One such reaction is the ruthenium-catalyzed directed o-C–
H arylation.10 The initial study of this reaction by Oi and In-
oue showed that coupling of 2-phenylpyridine with a stoi-
chiometric amount of aryl halide mediated by [RuCl2(p-cy-
mene)]2 (5 mol% Ru) and Ph3P (10 mol%) follows the same
reactivity trend as palladium-mediated cross-couplings,
namely PhI > PhBr > PhOTf > PhCl.11
DOI: 10.1055/s-0036-1588635; Art ID: st-2016-w0553-l
Abstract Functionalized aryl chlorides are more economically attrac-
tive but usually much more difficult as substrates in metal-mediated
couplings than the corresponding bromides and iodides. A catalyst pre-
pared from a bulky (biaryl)diphenyl phosphane and a common rutheni-
um source (1:1) mediates selective direct monoarylations of arenes
bearing 2-pyridyl and related ortho-directing groups in good yields. Se-
quential arylations to heterodiarylated products also proceed in satis-
factory yields.
Key words ruthenium, C–H activation, arylations, aryl chlorides,
phosphanes, heterocycles
Me
Me2N
Me
Aryl (pseudo)halides are important starting materials
for transition-metal-mediated cross-coupling reactions.1
Generally, a wider range of aryl chlorides are commercially
available at lower prices than aryl bromides, iodides, and
triflates. However, aryl chlorides are considerably less reac-
tive. The economic benefits of adopting aryl chlorides have
ignited a strong interest2 in their recruitment as substrates
in cross-coupling and direct arylation reactions.3 The intro-
duction of bulky, electron-rich N-heterocyclic carbenes
(NHC)4,5 and tertiary phosphanes,5,6 most active at li-
gand/palladium ratio 1:1,7 has successfully met that de-
mand. After extensive research, today it is clear that with
the choice of a suitable state-of-the-art ligand and palladi-
um source combination, the nature of the (pseudo)halide is
no longer a decisive factor for the success of the coupling.8
Biaryl-containing phosphanes has received the most at-
tention.9 Today, a significant number of the most powerful
(t-Bu)2P
NMe2
MeO
OMe
N
Me
PEt2
P(t-Bu)2
N
SO3Na
F
F
i-Pr
F
F
Ph
N
Ph
N
N
i-Pr
n-Bu
Me
N
N
Ph
P(t-Bu)2
i-Pr
P(Ad)2
PCy2
OMe
NMe2
P(t-Bu)2
N
PPh2
PCy2
Figure 1 Structurally diverse examples of commercially available, so-
phisticated biarylphosphane ligands
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
Y.-G. Li et al.
Letter
Synlett
For PhCl, only the monoarylated product was isolated in
32% yield. Shortly after, Ackermann et al. demonstrated that
much higher yields were attainable with bulky secondary
Cy2P
N
N
N
L2
PCy2
12
phosphane oxides/[RuCl2(p-cymene)]2 or the Grubbs sec-
L1
Me
Ph2P
Cy2P
ond-generation metathesis catalyst,13 which incorporates
two Cy3P ligands. Nevertheless, use of the common, inex-
pensive Ph3P14–18 as well as its more electron-rich tri(p-me-
thoxy-phenyl)phosphane17,19 continued in later studies.
Sporadic reports for use of other phosphane ligands such as
Cy3P,15,18 t-Bu3P,14 Bn3P,15 or dppb17 (dppb = 1,4-bis(diphen-
ylphosphino)butane) have surfaced without further in-
depth evaluation despite their demonstrated potential.
Surprisingly, the bulky, electron-rich biarylphosphane
ligands that have enjoyed such success in palladium cross-
coupling chemistry have not been explored to date in the
context of ruthenium-mediated direct arylations. Only two
reports of a detailed investigation of similar bulky (alke-
nyl)phosphane ligands exist.20 Perhaps, that is not surpris-
ing considering the emergence of the highly active rutheni-
um(dicarboxylate) catalysts.16,17,21 With phosphane ligands,
however, the monoarylated product predominates even
with an excess of the aryl halide.15 Under identical condi-
tions, the ruthenium(dicarboxylate) catalysts give very high
yields of diarylated products. Moreover, ruthenium-medi-
ated direct arylations have so far been investigated only for
relatively simple aryl chlorides.
N
N
L3
Me
L4
Me
[RuCl2(p-cymene)]2
(1 mol%)
L1–4 (2 mol%)
OMe
N
N
OMe
+
R
K2CO3 (2.5 equiv)
NMP, 120 °C, 24 h
1a
2a
Cl
3aa; R = H
4aa; R = p-MeOC6H5
Ligand
equiv 1a
equiv 2a
yield (3aa/4aa)
L1
L2
L3
L4
L3
1.0
1.0
1.0
1.0
1.2
2.2
2.2
2.2
2.2
1.0
6% (3:3)
50% (31:19)
94% (64:30)
12% (8:4)
94% (81:13)
b)
as above
no reaction
+
1a
(1.0 equiv)
Me
Me
2b(2.2 equiv)
Cl
Scheme 1 Initial evaluation of ligands L1–L4 for an electron-rich (a)
and sterically hindered (b) aryl chlorides (isolated yields)
[RuCl2(p-cymene)]2
(1 or 2.5 mol%)
L3 (2 or 5 mol%)
OMe
DG
OMe
DG
For our initial evaluation, we chose the most widely
used C–H activation substrate 1a, p-chloroanisole (2a;
Scheme 1, a), and 2-chloro-m-xylene (2b; Scheme 1, b)
with a representative set of heterobiarylphosphane ligands
L1–L4.22 In the presence of 2.2 equivalents of 2a, all ligands
gave predominantly the monoarylated product 3aa at 2
mol% catalyst loading. The combined yield (94%) was the
highest for L3. When 1a was used in excess (1.2 equiv rela-
tive to 4a), the same yield was obtained with even better
mono/di selectivity (3aa/4aa = 81:13). On the other hand,
substrate 2b gave no yield with any of the four ligands test-
ed at catalyst loading of 4 mol%. Next, we tested other C–H
activation substrates (1b–f; Scheme 2) with aryl chloride
2a. Among these, 1b was the most active giving 57% of the
monoarylated product 3ba. The rest (1c–f) only gave low to
moderate yields (3ca,d) even under more forcing conditions
(140 °C, 5 mol% catalyst). Particularly, the benzaldehyde
imine 1e was completely inactive.
Preparative couplings of 1a with a range of more com-
plex aryl chlorides (2c–t) proceeded in yields up to 81%
(3ac–at; Scheme 3). Phenyl chlorides carrying m- and p-
electron-donating (deactivating) substituents, including
free anilines (2c,d), phenols (2e,g), and aliphatic alcohols
(2f) coupled in high yields (63–81%). Similarly, the presence
of complex-forming substituents such as nitrile (2i, 61%) or
thioether (2h, 58%) was well tolerated. However, as known
from earlier works,12b,15,23 substrates containing an NO2
group were completely inactive, even under the forcing
+
K2CO3 (2.5 equiv), NMP
120 or 140 °C, 24 h
Cl 2a
3ba–fa
1b–f
(1.2 equiv) (1.0 equiv)
OMe
R
O
N
N
N
N
Bn
N
N
1d
1b
1c
R = H: 1e
R = Me: 1f
1ea: 0% (A, B)
1fa: 0% (A), 40 % (B)
(C=NAr C=O)*
57% (A) 16% (A), 25% (B)
48% (A)
Scheme 2 Evaluation of other C–H activation substrates with L3 (iso-
lated yields). Reagents and conditions: A: [RuCl2(p-cymene)]2 (1 mol%),
L3 (2 mol%), 120 °C; B: [RuCl2(p-cymene)]2 (2.5 mol%), L3 (5 mol%),
140 °C. *After hydrolysis with 1 N HCl (aq) over 3 h.
conditions specified above. Certain substituents in o-posi-
tion (Cl: 2j, 57%; Me: 2k, 58%; 2l, 80%) also did not hamper
the reaction. The presence of sulfur-containing heterocy-
cles (2l, 80%; 2s, 65%) was also well tolerated. On the other
hand, using complex nitrogen-containing heterocycles
showed a great variety in yields depending on the substitu-
tion pattern of the substrate. Coupling adjacent to pyridine
nitrogen (2m–o) was very sluggish under the standard con-
ditions (13–23%). The situation improved somewhat using
the forcing conditions specified above (31–37%). Coupling
of larger, heteroaryl chlorides proceeded better away from
the heteroatom (2p, 60%; 2t, 55%), especially under more
forcing conditions (2q, 78%; 2r, 46%).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
Y.-G. Li et al.
Letter
Synlett
rylated 3aa. Small amount of the two homodiarylated prod-
ucts (4aa) was also isolated. The yield of 5 improved signifi-
cantly (61%) when the second step was carried out at 140
°C.24 Under these conditions, the sequential reactions with
arylchlorides 2a/2d and 2d/2l gave the targeted heterodia-
rylated products 6 and 7 in satisfactory 54% and 41% yields,
respectively. In all cases, significant amounts (>14%) of un-
reacted monoarylated products (3aa,ad) were isolated.
That indicates that the second arylation step is retarded for
L3, and presumably other phosphane ligands catalyst. The
origin of this effect is unknown but it may be due to an in-
creased energetic cost of planarization of the 2-phenylpyri-
dine framework during the cycloruthenation step or de-
creased reactivity the product thereof with arylchlorides.
[RuCl2(p-cymene)]2
(1 or 2.5 mol%)
L3 (2 or 5 mol%)
Ar Cl
or
N
N
HetAr Cl
2c–t
(1.0 equiv)
+
(Het)Ar
K2CO3 (1.5 equiv), NMP
120 or 140 °C, 24 h
3ac–3at
1a (1.2 equiv)
N
Me
N
Me
OH
N
OMe
NH2
NH2
3ac: 80% (A)
3ad: 79% (A)
3ae: 81% (A)
O
N
N
OH
OH
3ag, 81% (A)
3af: 63% (A)
[RuCl2(p-cymene)]2
(1 mol%)
Ar2 Cl
N
N
N
SMe
N
F
(2.0 equiv)
L3 (2 mol%)
Ar1 Cl
(1.0 equiv)
+
T2 °C, 24 h
(same pot)
K2CO3 (2.5 equiv),
NMP, 120 °C, 24 h
CN
3ai: 61% (A)
Cl
3aj: 57% (A)
3ah: 58% (A)
1a (1.0 equiv)
Me
N
N
N
N
N
N
S
Ar1
Ar1
N
+
+
Ar1
Ar1
Ar1
N
Me
Me
Me
hetero-diarylated
(desired product)
3al: 80% (A)
3ak: 58% (A)
3am: 23% (A), 34% (B)
monoarylated
homo-diarylated
OMe
yield
Ar1
Ar2
T2
N
N
homo-di-
mono-
hetero-di-
N
N
N
N
NH2
120
140
14% (4aa) 44% (3aa) 43% (5)
18% 25% 61%
NH
3ap: 60% (A)
3ao: 13% (A),
Me
COOEt
3an: 20% (A), 31% (B)
OMe
37% (B)
2k
Me
3aq:
42% (A),
78% (B)
NH2
N
N
O
3ar:
0% (A)
140
140
16% (4aa) 15% (3aa) 54% (6)
N
2a
46% (B)
NH
N
NH
2d
2l
Me
NH2
O
Me
S
Me
16% (4ad) 28% (3ad) 41% (7)
N
N
2d
S
Scheme 4 Preparative sequential three-component direct arylations
3at: 55% (A)
3as: 65% (A)
with challenging aryl and heteroaryl chlorides (isolated yields)
Scheme 3 Preparative monoselective couplings of 2-phenylpyridine
with challenging aryl and heteroaryl chlorides (isolated yields). Reagents
and conditions: A: [RuCl2(p-cymene)]2 (1 mol%), L3 (2 mol%), 120 °C; B:
[RuCl2(p-cymene)]2 (2.5 mol%), L3 (5 mol%), 140 °C.
Finally, we evaluated couplings of C–H activation sub-
strates 1b and 1d with complex aryl chlorides (Scheme 5).
The initial evaluation (Scheme 2) demonstrated that sub-
strate 1d is more challenging than 1a and 1b. Hence, we
used more forcing conditions (5 mol% catalyst, 140 °C).
Moderate to good yields (products 3bc–ds, 31–76%) were
obtained for functionalized aryl chlorides 2c–e,g,i,p,s.
Herein we have demonstrated that a catalyst prepared
from a (heterobiaryl)diarylphosphane and [RuCl2(p-cy-
mene)]2 catalyzes directed o-arylations of a diverse set of
highly functionalized (hetero)aromatic chlorides. With re-
spect to o-directing groups, only 2-pyridyl, N-pyrazolyl, and
N-benzyl-2-imidazolyl gave synthetically acceptable yields,
The excellent monoselectivity attainable with L3/ruthe-
nium catalyst opens the possibility of multicomponent se-
quential directed C–H arylation with two separate aryl
chlorides.17,23 We evaluated the performance of L3/rutheni-
um catalyst in this application using some of the arylchlo-
rides that showed good performance for monoarylation
(Scheme 4). The sequential reaction of 1a with stoichiomet-
ric amount of p-chloroanisole (4a) and twofold excess of o-
chlorotoluene (2k; 2.0 equiv) gave a complex mixture, from
which the targeted heterodiarylated product 5 was isolated
in 43% (relative to 2a) along with 44% of unreacted monoa-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
Y.-G. Li et al.
Letter
Synlett
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DG
DG
Ar Cl
or
[RuCl2(p-cymene)]2
(1 or 2.5 mol%)
L3 (2 or 5 mol%)
(Het)Ar
+
HetAr Cl
3bc–ds
(1.0 equiv)
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K2CO3 (1.5 equiv), NMP
120 or 140 °C, 24 h
1b, d (1.2 equiv)
N
N
N
N
Me
OMe
NH2
N
N
NH2
3bd: 66% (A)
NH
3bc: 60% (A)
3bp: 46% (A)
O
N
N
N
N
OMe
Bn
3dc:
53% (B)
NH2
OH
3bg: 49% (A)
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39, 17.
N
N
F
Bn
Bn
N
N
Me
Bn
N
CN
3di: 38% (B)
N
O
S
OH
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3ds: 76% (B)
3de: 31% (B)
Scheme 5 Preparative monoselective couplings of substrates contain-
ing directing groups other than 2-pyridyl with challenging aryl and het-
eroaryl chlorides (isolated yields). Reagents and conditions: A: [RuCl2(p-
cymene)]2 (1 mol%), L3 (2 mol%), 120 °C; B: [RuCl2(p-cymene)]2 (2.5
mol%), L3 (5 mol%), 140 °C.
the latter two only under more forcing conditions and high-
er catalyst loading. The catalyst shows excellent selectivity
for monoarylation. Additionally, under forcing conditions
good yields of heterodiarylated products were obtained.
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Acknowledgment
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The authors thank Hefei University of Technology, Hong Kong Poly-
technical University (General Research Fund of Hong Kong, University
Grant Committee Grant PolyU 5010/13P) and Wuhan University of
Technology (China) for financial support.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588635.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
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H2O (40 mL) and EtOAc (20 mL). The organic phase was sepa-
rated and washed with H2O (3 × 30 mL), dried (MgSO4), filtered,
and concentrated under reduced pressure. Compounds 3aa
(65.3 mg, 25%; PE–EtOAc, 20:1), 4aa (64.6 mg, 18%; PE–EtOAc,
4:1), and 5 (214.4 mg, 61%; PE–EtOAc, 4:1) were sequentially
isolated after flash chromatography.
(24) Experimental Procedure
Two runs were set side by side. A Schlenk tube was loaded with
[RuCl2(p-cymene)]2 (3.1 mg, 5 μmol, 1 mol%), L3 (3.9 mg, 10
μmol, 2 mol%), and K2CO3 (173 mg, 1.25 mmol). The tube was
backfilled with Ar (3×). Under light backflow of Ar, NMP (0.5
mL) was added, followed by 1a (86 μL, 93 mg, 0.6 mmol) and p-
chloroanisole (2a; 62 μL, 71 mg, 0.5 mmol). The tube was sealed
and the reaction mixture was stirred at 120 °C for 24 h. After
cooling to r.t., under light backflow of Ar, o-chlorotoluene (2k;
59 μL, 63.3 mg, 0.5 mmol) was added, the tube was sealed, and
the reaction mixture was stirred 140 °C for 24 h. After cooling to
r.t., the reaction mixtures from both tubes were combined in
Compound 5: white solid, mp 107–108 °C. 1H NMR (600 MHz,
CDCl3): δ = 8.26 (d, J = 4.6 Hz, 1 H), 7.46 (dt, J = 7.6, 4.1 Hz, 2 H),
7.27 (s, 1 H), 7.08–6.96 (m, 7 H), 6.85 (dd, J = 11.4, 6.4 Hz, 2 H),
6.69 (d, J = 8.5 Hz, 2 H), 3.74 (s, 3 H), 2.05 (s, 3 H). 13C NMR (150
MHz, CDCl3): δ = 158.8, 158.0, 148.2, 141.5, 141.2, 141.0, 134.7,
134.0, 130.7–130.4 (multiple carbons), 129.3–128.8 (multiple
carbons), 127.8, 126.7, 126.1, 124.7, 120.7, 113.1, 113.1, 55.1,
20.3. ESI-HRMS: m/z [M + H]+ calcd for C25H22NO+: 352.1696;
found: 352.1698.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E