Direct ortho Arylation of Anisoles via the Formation of Four-Membered Lithiumcycles/Palladacycles

Article abstract of DOI:10.1055/s-0036-1588863

We report here our latest discovery on the directed lithiation and palladium-catalyzed arylation of anisoles. During this research, the formation of a four-membered lithiumcycle followed by transmetalation to the corresponding palladacycle has been achieved, which is difficult to be obtained from palladium-catalyzed C-H activation processes. This approach has provided an alternative way of introducing functionalities to arenes such as anisoles, thioanisoles, and anilines. This approach also features an excellent monoselectivity compared with reactions under transition-metal-catalyzed conditions.

Full text of DOI:10.1055/s-0036-1588863

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
X. Xiong et al.
Letter
Synlett
Direct ortho Arylation of Anisoles via the Formation of Four-Mem-
bered Lithiumcycles/Palladacycles
Xiaoyu Xiong◊a,b,c
Ranran Zhu◊a,b,c
Lin Huanga,b,c
DG
H
DG
Ar
1. nBuLi/TMEDA, Et2O
2. Pd2(dba)3, tBu3P, ArX
toluene, 0–50 °C
Shuqin Changa,b,c
Jianhui Huang*a,b,c
DG = OMe, NMe2, SEt, CH2NMe2
23 examples
a School of Pharmaceutical Science and Technology, Tianjin University,
Tianjin 300072, P. R. of China
jhuang@tju.edu.cn
b Collaborative Innovation Center of Chemical Science and Engineering,
Tianjin 300072, P. R. of China
c Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency,
P. R. of China
◊ These authors contributed equally
Received: 06.04.2017
Accepted after revision: 15.05.2017
Published online: 21.06.2017
formation of four-membered metallocycle 6 is very scarcely
studied. With anisole (4a) for example, the direct arylation
under transition-metal-catalyzed conditions would be very
challenging because the direct formation of four-mem-
bered metallocycle 6 from anisole (4a) is less favored
(Scheme 1, b). However, the use of the DoM (directed ortho-
metalation) strategy by directed ortho lithiation6 followed
by the transmetalation between lithium and a transition
metal such as palladium would be a good alternative to fa-
cilitate the formation of four-membered metallocycle 6.7–10
The further reaction of metallocycle 6 will lead to ortho-
substituted anisole 7 (Scheme 1, b).
DOI: 10.1055/s-0036-1588863; Art ID: st-2017-w0237-l
Abstract We report here our latest discovery on the directed lithiation
and palladium-catalyzed arylation of anisoles. During this research, the
formation of a four-membered lithiumcycle followed by transmetala-
tion to the corresponding palladacycle has been achieved, which is diffi-
cult to be obtained from palladium-catalyzed C–H activation processes.
This approach has provided an alternative way of introducing function-
alities to arenes such as anisoles, thioanisoles, and anilines. This ap-
proach also features an excellent monoselectivity compared with reac-
tions under transition-metal-catalyzed conditions.
Key words directed lithiation, lithiumcycle, transmetalation, mono-
selectivity, palladium-catalyzed arylation
N
N
N
1a
1b
M
The utilization of transition metals for the activation of
arene C–H bonds for further functionalization is one of the
most efficient strategies for the exploration of molecular di-
versity.1 The C–H activation of arenes with no coordinative
groups will normally lead to the products in less site-selec-
tive fashion. The introduction of directing groups in arenes
has attracted great attention for ortho-selective functional-
group installation.2 Our group has made contributions in
the direct access of heteroaromatic systems via ortho C–H
activation–annulation strategies.3 More interestingly, the
directed meta-4 and para-selective5 C–H activation have
been developed in the last five years. Within the field of di-
rected C–H activation under transition-metal-catalyzed
conditions, the formation of five-membered transition-
metal complexes are preferred intermediates, which could
give rise to the corresponding functionalized arenes. As
shown in Scheme 1 (a) with imine 1 as an example, the
five-membered metallocycle 2 is formed, which is then fur-
ther converted into the functionalized arene 3. The direct
FG
1
2
3
O
O
O
M
O
Li
FG
4a
5a
6
7
M = transition metal
FG = functional group
Scheme 1 Directed metalation–functionalization and directed lithia-
tion–transmetalation–functionalization of arenes
Tamoxifen (8, Figure 1), an anticancer agent11 which is
also being used for the treatment of the McCune–Albright
syndrome,12 is a drug molecule containing the anisole core
structure. Anisole derivatives or tamoxifen (8) could be
used as precursors for the further functionalization with
regard to the late-stage molecular modification for the lead
and optimizations for drug discovery.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
X. Xiong et al.
Letter
Synlett
Table 1 The Directed Lithiation and Trapping with Trimethylsilyl Chlo-
O
ridea
N
O
H
1. nBuLi, ligand, Et2O, temp.
2. TMSCl
O
TMS
Tamoxifen (8)
4a
7b
Figure 1 Anticancer agent tamoxifen 8
Entry
Ligand
Concn (M)
Temp (°C)
Yield of 7b (%)
1
2
3
4
5
6
–
0.4
0.4
0.2
0.4
0.4
0.4
r.t.
r.t.
r.t.
r.t.
0
21
99
99
92
97
79
In the directed ortho-lithiation process, the unique size
for the lithium ion makes a four-membered coordinative
intermediate possible. The directed lithiation followed by
the reaction with various electrophiles has been very well
studied.6 However, the direct lithiation and transmetalation
of organolithium with palladium for the direct introduction
of arenes has not been very well studied. Inspired by
Murahashi/Moritani9c and Feringa13, we explored directed
ortho-lithiation and palladium-catalyzed arylation process-
es. We herein report our latest discoveries on the directed
lithiation and palladium-catalyzed ortho arylation for the
access of a class of arylated anisole derivatives as shown in
Scheme 2.
TMEDA
TMEDA
PMDTA
TMEDA
TMEDA
–20
a Reaction conditions: anisole 4a (0.2 mmol), n-BuLi (2.4 M, 0.125 mL, 1.5
equiv), TMEDA (34.8 mg, 1.5 equiv) in Et2O (0.4 M, 0.5 mL), r.t. 0.5 h,
TMSCl (0.1 mL).
Table 2 The Directed Lithiation and Palladium-Catalyzed Arylationa
1. nBuLi/TMEDA (1.5 equiv),
Et2O, rt, 0.5 h
O
H
O
O
H
O
1. nBuLi/TMEDA
2. Pd (cat.), ligand, PhX,
toluene, temp.
Ph
2. Pd (cat.), ligand, PhI
Ph
4a
7a
4a
7a
O
O
Li
PPh2
PPh2
Pd
PCy2
iPr
PCy2
NMe2
PCy2
OMe
iPr
O
MeO
5
6a
Scheme 2 The directed lithiation–four-membered palladacycle forma-
tion for the ortho arylation
iPr
XPhos
SPhos
DavePhos
XantPhos
Entry PhX
Pd catalyst
Ligand
Temp (°C) Yield of 7a (%)
We chose anisole (4a) as our model substrate for the
lithiation reactions. As one of our research focus, we were
interested in the utilization of n-BuLi under mild conditions
instead of the less stable and more expensive t-BuLi and s-
BuLi for the deprotonation at low temperature. A number of
commonly available amine ligands were studied. The lithia-
tion at room temperature in the absence of a ligand was in-
efficient; the desired silylated anisole 7b was isolated in
21% yield after lithiation and trapping with TMSCl (Table 1,
entry 1). The use of TMEDA at both 0.4 M and 0.2 M were
both giving the desired product in nearly quantitative yield
(Table 1, entries 2 and 3). The triamine additive PMDTA14
with n-BuLi was nearly as good as the use of TMEDA (Table
1, entry 4). The results from the reaction at 0 °C are compa-
rable to those at room temperature, however, the reaction
at –20 °C provided the desired arene 7b in slightly lower
yield of 79% (Table 1, entries 5 and 6).
1
2
PhBr
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(Pt-Bu3)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
XPhos
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
12
6
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PhI
SPhos
3
DavePhos
XantPhos
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
<5
<5
34
10
12
31
49
57
65
4
5
6
7
8
9
10
11a
50
PhI
0-50
a Reaction conditions: anisole 4a (0.2 mmol), n-BuLi (2.4 M, 0.125 mL, 1.5
equiv), TMEDA (34.8 mg, 1.5 equiv) in Et2O (0.4 M, 0.5 mL), r.t. 0.5 h, then
aryl halides (ArX, X = Br or I, 2 equiv), Pd2(dba)3 (9.2 mg, 5 mol%) and
P(t-Bu)3 (1.0 M in toluene, 0.04 mL, 20 mol%) in toluene (0.4 mL).
b The lithiated reaction mixture was added at 0 °C then warm up to 50 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
X. Xiong et al.
Letter
Synlett
With the optimal conditions for the lithiation step in
hand, the transition-metal catalyst/ligand screening was
also carried out. In order to speed up the oxidative addition
processes, a number of electron-rich phosphine ligands was
evaluated. After treatment of lithiated anisole 4a with 5
mol% of Pd2(dba)3 in the presence of 20% of XPhos ligand at
room temperature for three hours, the desired arylated
product 3b was isolated in 12% yield (Table 2, entry 1). Bi-
aryl phosphine ligands such as SPhos, DavePhos, and Xant-
Phos were also examined; unfortunately, the desired prod-
uct 7a was only isolated in rather low yields (Table 2, en-
tries 2–4). The increase of the reaction temperature to 50 °C
led to the desired product 7a in 49% yield (Table 2, entry 9).
The addition of organolithium prepared at 0 °C then slowly
warm up to 50 °C. The use of PhI instead of PhBr gave the
desired product in 57% yield (Table 2, entry 10). Compared
to the lithium–palladium coupling reactions developed by
Feringa, where they were calculated reaction yields based
on the use of aryl halides with excess use of commercially
available organolithium reagents, our yields were calculat-
ed based on the amount of anisoles used.
1. nBuLi/TMEDA, Et2O
O
O
H
2. Pd2(dba)3, tBu3P, ArX
toluene, 0–50 °C
Ar
4a
7
OMe
OMe
OMe
Ph
OMe
Cl
NO2
F
X = I 7a (65%)
X = Br 7a (57%)
X = I 7e (22%)a
X = I 7c (41%)
X = I 7d (63%)
OMe
OMe
OMe
OMe
OMe
X = I 7h (66%)
X = Br 7h (64%)
X = I 7f (55%)
X = I 7g (53%)
X = I 7i (67%)
OMe
OMe
OMe
OMe
N
X = I 7j (34%)
X = Br 7j (42%)
X = I 7k (49%)
X = I 7l (62%)
X = Br 7m (30%)
Under our optimized conditions, reactions with a num-
ber of aryl halides were evaluated. The corresponding ary-
lated products with aryl halides were all successfully ob-
tained in useful to good yields (Scheme 3). Reactions of
arenes bearing both electron-rich and electron-deficient
substituents at the para position went smoothly and the
desired products 7a–g were obtained. More interestingly,
coupling reactions for the introduction of bicyclic and tricy-
clic ring systems have also shown to be fruitful, the corre-
sponding arylated products 7j–l were successfully obtained.
In addition, coupling with a heteroaromatic system is also
possible; the desired product 7m was isolated in 30% yield.
The utilization of alkyl bromides and chloride were also
studied. It seemed that the reactions with alkyl bromides
gave similar results as the ones using alkyl iodides, howev-
er, reaction with alkyl chloride was less efficient due to the
low conversion.
Reactions with a number of representative directed
arenes were also evaluated. The results are shown in
Scheme 4. The use of substituted anisoles provided the cor-
responding phenyl-substituted anisoles in moderate to use-
ful yields. The low yielding with halo-substituted anisoles is
due to the strong base mediated reduction reaction. The de-
halogenated product 7a was formed together with our de-
sired products 7n and 7o, respectively. The side reaction
was even more favored when meta-Cl-substituted anisole
was utilized. No desired product formed with only 10% of
anisole, 7a was isolated. The N- and S-containing directing
groups have also been demonstrated to be efficient lithia-
tion directing groups for the palladium-catalyzed direct
arylation processes. Tamoxifen derivatives 8a and 8b have
also been obtained albeit with low yields.
Scheme 3 Synthesis of monoarylated anisoles. Reagents and condi-
tions: anisole 4a (0.2 mmol), n-BuLi (2.4 M, 0.125 mL, 1.5 equiv),
TMEDA (34.8 mg, 1.5 equiv) in Et2O (0.4 M, 0.5 mL), r.t. 0.5 h, then aryl
halides (ArX, X = Br or I, 2 equiv), Pd2(dba)3 (9.2 mg, 5 mol%) and
P(t-Bu)3 (1.0 M in toluene, 0.04 mL, 20 mol%) in toluene (0.4 mL), 0–50
°C. a Transmetalation with ZnCl2 (2.0 equiv) proceeded.
The proposed reaction mechanism is shown in Scheme
5. The reaction starts from the addition of a palladium(0)
species in the presence of an electron-rich ligand onto ArX
to give palladium(II) intermediate 9. After the ligand deas-
sociation, palladium species 10 forms. Transmetalation oc-
curs when lithiated anisole 5 reacts with palladium species
10 to provide the four-membered palladacycle 11. The
transmetalation processes between organolithium and aryl
palladium species have been studied previously in the
Murahashi group.15 The desired product 7a is obtained after
reductive elimination of palladium complex 11 to regener-
ate the palladium(0) catalyst which is ready for the next
catalytic cycle.
In conclusion, we have studied the directed lithiation
procedure as well as the direct transmetalation processes
for the access of arylated anisoles in useful to good yields.16
This has made the direct arylation of anisoles possible as a
good alternative for access a range of anisoles, thioanisoles,
and anilines.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
X. Xiong et al.
Letter
Synlett
Funding Information
DG
H
DG
Ar
1. nBuLi/TMEDA, Et2O
The financial support from the ‘973’ Program (2015CB856500), the
NSFC (Grant No. 21672159, 21302136), and Tianjin Natural Science
Foundation (Grant No. 13JCQNJC04800) are gratefully acknowledged.
2. Pd2(dba)3, tBu3P, PhI
toluene, 0–50 °C
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Supporting Information
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Supporting information for this article is available online at
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References and Notes
7q (0%)
7r (24%)
7s (28%)
7t (60%)
S
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S
NMe2
Ph
Cl
7u (50%)
7v (45%)
7w (26%)
O
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Cl
OMe
8a (27%)
8b (19%)
Scheme 4 Direct arylation of various arenes. Reagents and conditions:
arene 4 (0.2 mmol), n-BuLi (2.4 M, 0.125 mL, 1.5 equiv), TMEDA (34.8
mg, 1.5 equiv) in Et2O (0.4 M, 0.5 mL), r.t. 0.5 h, then PhI (2 equiv),
Pd2(dba)3 (9.2 mg, 5 mol%) and P(t-Bu)3 (1.0 M in toluene, 0.04 mL, 20
mol%) in toluene (0.4 mL).
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O
Pd(0)/L
Ph
ArX
oxidative
7a
reductive
X = I, Br, Cl
addition
elimination
Ar
O
L
L
Pd
X
Pd
Ar
11
9
ligand deassociation
Ar
transmetallation
Pd
X
nBuLi
TMEDA
O
H
O
Li
10
5
4a
directed ortho lithiation
Scheme 5 The plausible reaction mechanism
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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(d) Achonduh, G. T.; Hadei, N.; Valente, C.; Avola, S.; O'Brien, C.
J.; Organ, M. G. Chem. Commun. 2010, 46, 4109. (e) Colombe, J.
R.; Bernhardt, S.; Stathakis, C.; Buchwald, S. L.; Knochel, P. Org.
Lett. 2013, 15, 5754.
(8) Selected recent literature in Li–Mg transmetalation:
(a) Rosquete, L. I.; Cabrera-Serra, M. G.; Piñero, J. E.; Martín-
Rodríguez, P.; Fernández-Pérez, L.; Luis, J. G.; McNaughton-
Smith, G.; Abad-Grillo, T. Bioorg. Med. Chem. 2010, 18, 4530.
(b) Lau, S. Y.; Hughes, G.; O'Shea, P. D.; Davies, I. W. Org. Lett.
2007, 9, 2239. (c) Sun, K.; Wang, L.; Wang, Z. X. Organometallics
2008, 27, 5649. (d) Chen, M. T.; Lee, W. Y.; Tsai, T. L.; Liang, L. C.
Organometallics 2014, 33, 5852. (e) Wang, Z. X.; Chai, Z. Y. Eur. J.
Inorg. Chem. 2007, 4492.
(9) Selected recent literature in Li–Pd transmetalation: (a) Lu, J. Y.;
Wan, H.; Zhang, J.; Wang, Z.; Li, Y.; Du, Y.; Li, C.; Liu, Z. T.; Liu, Z.
W.; Lu, J. Chem. Eur. J. 2016, 22, 17542. (b) Vila, C.; Hornillos, V.;
Giannerini, M.; Fañanás-Mastral, M.; Feringa, B. L. Chem. Eur. J.
2014, 20, 13078. (c) Murahashi, S. I.; Tanba, Y.; Yamamura, M.;
Moritani, I. Tetrahedron Lett. 1974, 15, 3749. (d) Shen, Q.;
Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 10028. (e) Smith, A. B.
III.; Hoye, A. T.; Martinez-Solorio, D.; Kim, W. S.; Tong, R. J. Am.
Chem. Soc. 2012, 134, 4533. (f) Martinez-Solorio, D.; Melillo, B.;
Sanchez, L.; Liang, Y.; Lam, E.; Houk, K. N. J. Am. Chem. Soc. 2016,
138, 1836. (g) Murahashi, S.; Tamba, Y.; Yamamura, M.;
Yoshimura, N. J. Org. Chem. 1978, 43, 4099. (h) Lee, S.;
Jørgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729.
(13) (a) Buter, J.; Heijnen, D.; Vila, C.; Hornillos, V.; Otten, E.;
Giannerini, M.; Minnaard, A. J.; Feringa, B. L. Angew. Chem. Int.
Ed. 2016, 55, 3620. (b) Pinxterhuis, E. B.; Giannerini, M.;
Hornillos, V.; Feringa, B. L. Nat. Commun. 2016, 7. (c) Vila, C.;
Giannerini, M.; Hornillos, V.; Fañanás-Mastral, M.; Feringa, B. L.
Chem. Sci. 2014, 5, 1361. (d) Giannerini, M.; Fañanás-Mastral,
M.; Feringa, B. L. Nat. Chem. 2013, 5, 667. (e) Fañanás-Mastral,
M.; Pérez, M.; Bos, P. H.; Rudolph, A.; Harutyunyan, S. R.;
Feringa, B. L. Angew. Chem. Int. Ed. 2012, 51, 1922. (f) Pérez, M.;
Fañanás-Mastral, M.; Bos, P. H.; Rudolph, A.; Harutyunyan, S. R.;
Feringa, B. L. Nat. Chem. 2011, 3, 377.
(14) (a) Wang, Y.; Liu, J.; Huang, L.; Zhu, R.; Huang, X.; Moir, R.;
Huang, J. Chem. Commun. 2017, 53, 4589. (b) Klumpp, G. W.;
Luitjes, H.; Schakel, M.; de Kanter, F. J. J.; Schmitz, R. F.; van
Eikema Hommes, N. J. R. Angew. Chem. Int. Ed. 1992, 31, 633.
(15) (a) Murahashi, S-I.; Yamamura, M.; Yanagisawa, K-I.; Mita, N.;
Kondo, K. J. Org. Chem. 1979, 44, 2408. (b) Murahashi, S-I.;
Tamba, Y.; Yamamura, M.; Yoshimura, N. J. Org. Chem. 1978, 43,
4099.
(16) General Procedure for Direct ortho Arylation of Anisoles
A 5 mL well-dried round-bottomed flask was charged with
nitrogen through Schlenk line. To a solution of the correspond-
ing substrate (0.2 mmol) and TMEDA (34.8 mg, 1.5 equiv) in
Et2O (0.4 M, 0.5 mL), n-BuLi (2.4 M, 0.125 mL, 1.5 equiv) was
added dropwise at r.t. Then the reaction was allowed to stir for
0.5 h at r.t.
In another 10 mL well-dried flask, the aryl halides (ArX, X = Br
or I, 2 equiv), Pd2(dba)3 (9.2 mg, 5 mol%) and P(t-Bu)3 (1.0 M in
Tol, 0.04 mL, 20 mol%) were dissolved in toluene (0.4 mL), and
the solution was stirred for 5 min. Then the above organolith-
ium solution was added dropwise at 0 °C, and the reaction was
then allowed to stir at 50 °C for another 3 h. The mixture was
quenched with sat. aq NH4Cl, extracted with EtOAc (3 × 5 mL),
dried over anhydrous Na2SO4, filtered, and concentrated under
vacuo. The residue was purified by column chromatography to
get the product.
(Z)-2-{[5-(1,2-Diphenylbut-1-en-1-yl)-3′-methoxy-(1,1′-
biphenyl)-2-yl]oxy}-N,N-dimethylethanamine (8a)
Following the general procedure, the amine 8a was obtained
after column chromatography as a colorless oil (X = I, 26 mg, 27
% yield). 1H NMR (600 MHz, CDCl3): δ = 7.35 (t, J = 6.5 Hz, 2 H),
7.29–7.20 (m, 5 H), 7.19–7.13 (m, 4 H), 6.86 (s, 1 H), 6.77 (d, J =
8.0 Hz, 2 H), 6.69 (m, 2 H), 6.64 (d, J = 8.0 Hz, 1 H), 3.94 (t, J = 5.0
Hz, 2 H), 3.76 (s, 3 H), 2.59 (t, J = 5.0 Hz, 2 H), 2.46 (q, J = 6.5 Hz,
2 H), 2.21 (s, 6 H), 0.93 (t, J = 7.0 Hz, 3 H). 13C NMR (151 MHz,
CDCl3): δ = 158.9, 153.7, 143.6, 142.6, 141.6, 139.8, 138.1, 135.7,
133.7, 130.8, 129.8, 129.5, 129.3, 128.4, 128.1, 128.0, 126.6,
126.1, 122.2, 114.7, 112.7, 111.6, 66.7, 58.0, 55.3, 45.9, 29.1,
13.6. ESI-HRMS: m/z [M + H]+ calcd for (C33H36NO2): 478.2746;
found: 478.2745.
(10) Selected recent literature in Li transmetalation with other
metals: (a) Jia, Z.; Liu, Q.; Peng, X. S.; Wong, H. N. Nat. Commun.
2016, 7. (b) Jhaveri, S. B.; Carter, K. R. Chem. Eur. J. 2008, 14,
6845. (c) Nagaki, A.; Kenmoku, A.; Moriwaki, Y.; Hayashi, A.;
Yoshida, J. I. Angew. Chem. 2010, 122, 7705.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E