Suzuki-Miyaura Cross-Coupling Reactions in Acetic Acid Employing Sydnone-Derived Catalyst Systems

Article abstract of DOI:10.1055/s-0036-1589059

The catalyst system consisting of lithium N -phenylsydnone-4-carboxylate/Pd(PPh ₃) ₄ has proven to be an effective catalyst for the Suzuki-Miyaura reaction of 2,4-dinitrochlorobenzene with boronic acids in acetic acid at pH 5.7, wher

Full text of DOI:10.1055/s-0036-1589059

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
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A
en
A.-L. Lücke et al.
Letter
Synlett
Suzuki–Miyaura Cross-Coupling Reactions in Acetic Acid Employing
Sydnone-Derived Catalyst Systems
Ana-Luiza Lücke
ArB(OH)2
cat. (10 mol%)
1,4-dioxane, H2O
70 °C, 30 min
Sascha Wiechmann
O2N
NO2
Cl
O2N
NO2
Tyll Freese
Andreas Schmidt*
pH 4–8
Ar
up to 99%
Clausthal University of Technology, Institute of Organic Chemistry,
Leibnizstrasse 6, 38678 Clausthal-Zellerfeld, Germany
schmidt@ioc.tu-clausthal.de
O
cat. 1:
cat. 2:
PdBr(PPh3)2
O–
Li /
R
R
N
N
N
N
Pd(PPh3)4
O
O–
O
O–
Ar = Ph, 3-tolyl, 1-naphthyl, 9-phenanthryl, thiophen-2-yl,
4-biphenyl, 4-MeSC6H4, 4-F3COC6H4
Li+
–
Li+
O
Received: 31.03.2017
Accepted after revision: 20.05.2017
Published online: 29.06.2017
H/Br
O–
Ph
Ph
Ph
N
N
N
N
N
N–
BuLi
O
O–
DOI: 10.1055/s-0036-1589059; Art ID: st-2017-b0222-l
O
O
1
2
Abstract The catalyst system consisting of lithium N-phenylsydnone-
4-carboxylate/Pd(PPh3)4 has proven to be an effective catalyst for the
Suzuki–Miyaura reaction of 2,4-dinitrochlorobenzene with boronic ac-
ids in acetic acid at pH 5.7, whereas the N-phenylsydnone carbene pal-
ladium complex [sydPd(PPh3)2Br] required pH 8.0.
[PdX2(PPh3)2]
PdX(PPh3)2
CO2
O
Ph
O–
Li+
Ph
N
N
N
N
O
O–
O
O–
Key words catalysis, Suzuki–Miyaura reaction, N-heterocyclic carbenes,
4
sydnones, palladium, pH value
3
Scheme 1 Sydnones, anionic sydnone carbenes, and derivatives
The Suzuki–Miyaura cross-coupling is one of the most
important transition-metal-catalyzed C–C coupling reac-
tion in organic chemistry.1 Mild reaction conditions, the
commercial availability of numerous organoboron com-
pounds, and the toleration of a broad variety of functional
groups are inestimable advantages of the Suzuki–Miyaura
reaction in comparison to other cross-couplings.2 The reac-
tion has proven to fail in the absence of bases, however,
which sometimes induce side reactions such as racemiza-
tion of asymmetric carbon atoms or aldol condensations.2
In continuation of our interest in mesomeric betaines,3 N-
heterocyclic carbenes (NHCs)4,5 and their application in
catalysis6,7 we report here on our preliminary results of
Suzuki–Miyaura reactions in the presence of sydnone-de-
rived catalyst systems which give best yields in dependence
of the pH of the reaction mixture, covering the range from
strongly basic to acidic media. Sydnones 18 are conjugated
mesomeric betaines9 which belong to the subclass of meso-
ionic compounds (Scheme 1).10 On deprotonation they give
unique anionic NHCs 2 which can be regarded as anionic
abnormal NHCs or anionic NHCs depending on the favored
mesomeric structure.5 Sydnone carbenes 2 and their deriv-
atives can be trapped by CO2 as sydnone carboxylates 3 or
as palladium complexes 4.5 The latter have already proved
to be catalytically active.5,7 Efficient procedures to prepare
311and 412 start from 4-halosydnones and lithium bases.
The relationship between mesomeric betaines including
mesoionic compounds and NHCs has been summarized in a
review article.13 In order to test the catalytic properties of
sydnone-4-carboxylate 3 and of the sydnone carbene palla-
dium complex 4 we performed a catalyst screening and
compared the results with other catalysts for the Suzuki–
Miyaura reaction. We chose the cross-coupling of 1-chloro-
2,4-dinitrobenzene (5) with phenylboronic acid 6a
PhB(OH)2 (6a),
cat. 1–6 (10 mol%),
1,4-dioxane, 70 °C,
30 min,
O2N
NO2
Cl
O2N
NO2
Ph
various conditions
5
7a
Scheme 2 Model Suzuki–Miyaura reaction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
A.-L. Lücke et al.
Letter
Synlett
(Scheme 2) as model reaction and examined six different
catalyst systems, which are listed in Table 1, under identical
conditions.
without sodium carbonate at pH 4.0 gave considerably de-
creased yields (Table 3, entry 2). Excellent yields, however,
were obtained at pH 5.7 in the presence of acetic acid as
well as sodium carbonate (1:1, Table 3, entry 3). By con-
trast, performing the reaction without sodium carbonate
under acidic conditions (Table 3, entries 4, 6) or without
water (Table 3, entry 5)15 gave only low yields of 7a when
the sydnone palladium complex (cat. 2) was employed,
whereas a pH value of 8.0 gave quantitative yields as men-
tioned before (cf. Table 1, entry 2). The catalyst systems 3–6
either failed or gave low to moderate yields at pH 5.7 (Table
3, entries 7–9 and 12). Palladium acetate in acetic acid at pH
4.0 failed almost completely as catalyst (Table 3, entry 10),
whereas its catalysis at pH 6.5 gave moderate yields (Table
3, entry 11) of 7a.
Table 1 Six Catalyst Systems Tested in a Model Reaction
Catalyst system
Ingredients
cat. 1
cat. 2
cat. 3
cat. 4
cat. 5
cat. 6
sydnone carboxylate 3, Pd(PPh3)4
sydnon palladium complex 4
sydnone 1, Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
PdCl2(PPh3)2
At pH 8.0 the catalyst system consisting of lithium syd-
none-4-carboxylate 3 and Pd(PPh3)4 (cat. 1) gave only low
yields of 2,4-dinitro-1,1′-biphenyl (7a) and 1-(2,4-dinitro-
phenyl)naphthalene (7b, Table 2, entries 1 and 7). In con-
trast to catalysis systems cat. 3–6 (Table 2, entries 3–6), the
catalysis by the sydnone carbene palladium complex 4 (cat.
2) gave excellent to quantitative yields of 7a and 7b at pH
Table 3 Yields of the Model Reaction between 5 and Phenylboronic
Acid (6a) to Give 7a Employing Cat. 1–6 at Various pH Values
Entry
Reaction conditionsa
pH
6.5
Yield (%)f
1
2
cat. 1, H2Ob
37
18
91
15
<10
50
15
0
cat. 1, H2O, AcOHc
cat. 1, H2O, AcOH, Na2CO3
cat. 2, H2O, AcOHc
4.0
5.7
4.0
–
d
3
8.0 (Table 2, entries
2
and 8).5 1-(2,4-Dinitrophe-
4
nyl)phenanthrene (7c) was obtained in 80% yield (Table 2,
entry 9).7 Under these conditions, cat. 2 is among the best
catalyst systems for this reaction.14
e
5
cat. 2, Na2CO3
d
d
d
d
6
cat. 2, H2O, AcOH, Na2CO3
cat. 3, H2O, AcOH, Na2CO3
cat. 4, H2O, AcOH, Na2CO3
cat. 5, H2O, AcOH, Na2CO3
cat. 5, H2O, AcOHc
5.7
5.7
5.7
5.7
4.0
6.5
5.7
7
Table 2 Yields of the Suzuki–Miyaura Reaction of 5 with Boronic Acids
6a–c Employing the Catalyst Systems 1–6 at pH 8.0
8
9
45
<5
61
0
Entry
Ar
6a Ph
Reaction conditionsa Yield (%)b
10
11
12
cat. 5, H2Ob
1
2
3
4
5
6
7
8
9
cat. 1
cat. 2
cat. 3
cat. 4
cat. 5
cat. 6
cat. 1
cat. 2
cat. 2
7a 38
7a 99
7a 78
7a 82
7a 81
7a 60
7b 32
7b 95
7c 80
d
cat. 6, H2O, AcOH, Na2CO3
6a Ph
aReaction conditions: catalyst systems (10 mol%), respectively, of 1,4-diox-
ane (8 mL), 5 (0.2 mmol), 6a (2 equiv). Variations:
b2 mL of water.
6a Ph
6a Ph
c17 mmol of AcOH, 2 mL water.
d4.7 mmol of Na2CO3, 17 mmol of AcOH, 2 mL of water.
e4.7 mmol of Na2CO3.
6a Ph
6a Ph
fIsolated yields after chromatography.
6b 1-naphthyl
6b 1-naphthyl
6c 9-phenanthryl
We applied the optimized reaction conditions of the
Suzuki–Miyaura reaction in the presence of sydnone car-
boxylate 3 and Pd(PPh3)4 (cat. 1) in acetic acid at pH 5.7 to
other boronic acids which gave new products 7c–h (Table
4).16 1-Naphthyl boronic acid gave a very good yield of 7b in
an acidic medium (Table 4, entry 1). As a comparison, under
analogous reaction conditions, the sydnone palladium com-
plexes achieved only 43% of 7b in acid, whereas 95% were
formed under basic conditions at pH 8.0 (cf. Table 2, entry
8). Under acidic conditions the formation of 1-(2,4-dinitro-
phenyl)phenanthrene 7c is even more effective with cat. 1
than under basic conditions and cat. 2 (Table 4, entry 3). 3′-
Methyl-2,4-dinitro-1,1′-biphenyl (7d) was formed in mod-
erate yield under these conditions (Table 4, entry 4). 2-(2,4-
aReaction conditions: catalyst systems (10 mol%), respectively, 1,4-dioxane
(8 mL), 5 (0.2 mmol), 6a–c (2 equiv), respectively, Na2CO3 (4.7 mmol), wa-
ter (2 mL).
bIsolated yields after chromatography; for conditions, cf. Scheme 2.
In order to find optimized reaction conditions for the
reaction in the presence of the sydnone-4-carboxylate-de-
rived catalyst system (cat. 1), we varied the reaction condi-
tions by adjusting the pH value of the reaction mixture by
addition of sodium carbonate and acetic acid (Table 3). Ad-
dition of neither of these ingredients gave only 37% yield of
7a (Table 3, entry 1). Performing the reaction in acetic acid
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
A.-L. Lücke et al.
Letter
Synlett
Dinitrophenyl)thiophene (7e), 2,4-dinitro-1,1′:4′,1′′-ter-
phenyl (7f), 2′,4′-dinitro-(1,1′-biphenyl)-4-thiol (7g), and
2,4-dinitro-4′-(trifluoromethoxy)-1,1′-biphenyl (7h) were
formed in very good yields by Suzuki–Miyaura reaction in
acid (Table 4, entries 5–8).
In summary, we demonstrated that the catalyst systems
consisting of sydnone carboxylate 3 and Pd(PPh3)4 (cat. 1)
required acidic conditions (pH 5.7) to give good to excellent
yields of Suzuki–Miyaura cross-couplings, whereas the syd-
none carbene palladium complex 4 needed basic conditions
(pH 8.0).
Table 4 Yields of the Model Reaction at pH 5.7
Funding Information
Entry Ar
Reaction conditionsa Yield (%)b
The Deutsche Forschungsgemeinschaft (DFG) is gratefully acknowl-
1
2
3
4
5
6
7
8
6b 1-naphthyl
cat. 1
cat. 2
cat. 1
cat. 1
cat. 1
cat. 1
cat. 1
cat. 1
7b 91
7b 43
7c 91
7d 53
7e 94
7f 91
7g 89
7h 86
edged for financial support
??
?(?)
6b 1-naphthyl
6c 9-phenanthryl
6dm-tolyl
Supporting Information
6e 2-thiophen
Supporting information for this article is available online at
https://doi.org /10.1055/s-0036-1589059.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
6f 4-biphenyl
6g 4-(methylthio)phenyl
6h 4-(trifluoromethoxy)phenyl
References and Notes
aReaction conditions: Cat. 1 or 2 (10 mol%), 1,4-dioxane (8 mL), 5 (0.2
mmol), 6a–h (2 equiv), Na2CO3 (4.7 mmol), AcOH (17 mmol), water (2
mL).
(1) (a) Guram, A. S.; Milne, J. E.; Tedrow, S.; Walker, S. D. In Science
of Synthesis;
2
V0o.1l25/ Molander, G.-A., Ed.; Thieme: Stuttgart, 2012, 9.
bIsolated yields after chromatography.
(b) De Meijere, A.; Bräse, S.; Oestreich, M. Metal-Catalyzed
Cross-Coupling Reactions and More; Wiley-VCH: Weinheim,
2014. Some recent reviews: (c) Mo, S.; Zhang, Z.; Zhang, G.;
Ding, Y.; Li, Q. H. Curr. Org. Synth. 2017, 14, 462. (d) Almond-
Thynne, J.; Blakemore, D. C.; Pryde, D. C.; Spivey, A. C. Chem. Sci.
2017, 8, 40. (e) Li, C.; Chen, D.; Tang, W. Synlett 2016, 27, 2183.
(f) Hussain, I.; Capricho, J.; Yawer, M. A. Adv. Synth. Catal. 2016,
358, 3320. (g) Oger, N.; Felpin, F.-X. ChemCatChem. 2016, 8,
1998. (h) Das, P.; Linert, W. Coord. Chem. Rev. 2016, 311, 1.
(i) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C.; Marianetti, G.;
Perego, L. A. Curr. Org. Chem. 2015, 19, 1302. (j) Maluenda, I.;
Navarro, O. Molecules 2015, 20, 7528. (k) Paul, S.; Islam, M. M.;
Islam, S. M. RSC Adv. 2015, 5, 42193. (l) Fyfe, J. W. B.; Watson, A.
J. B. Synlett 2015, 26, 1139. (m) Glasspoole, B. W.; Keske, E. C.;
Crudden, C. M. RSC Catal. Ser. 2015, 21, 521. (n) Lennox, A.;
Lloyd-Jones, G. RSC Catal. Ser. 2015, 21, 322. (o) Zhang, D.;
Wang, Q. Coord. Chem. Rev. 2015, 286, 1.
Finally, we examined the role of sodium acetate and car-
ried out a series of reactions of 2,4-dinitrochlorobenzene
(5) and phenylboronic acid (6a) in the presence of the syd-
none carbene palladium complex (cat. 2). As shown in Table
5, the presence of water is necessary, and best results were
achieved when sodium acetate, sodium carbonate, and wa-
ter were present (Table 5, entry 5). These conditions repre-
sent an alternative procedure to those shown in Table 2 (en-
try 2).
Table 5 Yields of the Model Reaction of 5 and 6a in the Presence of
Cat. 2 (10 mol%) and Sodium Acetate
(2) (a) Kürti, L.; Czakó, B. Strategic Applications of Named Reactions
in Organic Synthesis; Elsevier Academic Press: Amsterdam,
2005, 448. (b) Willemse, T.; Schepens, W.; van Vlijemen, H. W.
T.; Maes, B. U. W.; Ballet, S. Catalysts 2017, 7, 74. (c) Prieto, M.;
Mayor, S.; Lloyd-Williams, P.; Giralt, E. J. Org. Chem. 2009, 74,
9202. (d) Prieto, M.; Mayor, S.; Rodríguez, K.; Lloyd-Williams, P.;
Giralt, E. J. Org. Chem. 2007, 72, 1047.
(3) (a) Schmidt, A.; Batsyts, S.; Smeyanov, A.; Freese, T.; Hübner, E.
G.; Nieger, M. J. Org. Chem. 2016, 81, 4202. (b) Liu, M.; Nieger,
M.; Schmidt, A. Chem. Commun. 2015, 51, 477. (c) Schmidt, A.;
Kindermann, M. K. J. Org. Chem. 1997, 62, 3910.
(4) (a) Liu, M.; Nieger, M.; Hübner, E.; Schmidt, A. Chem. Eur. J.
2016, 22, 5416. (b) Schmidt, A.; Münster, N.; Dreger, A. Angew.
Chem. Int. Ed. 2010, 49, 2790; Angew. Chem. 2010, 122, 2851.
(5) Wiechmann, S.; Freese, T.; Drafz, M. H. H.; Hübner, E. G.;
Namyslo, J. C.; Nieger, M.; Schmidt, A. Chem. Commun. 2014, 50,
11822.
(6) (a) Rahimi, A.; Pápai, I.; Madarász, Á.; Gjikaj, M.; Namyslo, J. C.;
Schmidt, A. Eur. J. Org. Chem. 2012, 754. (b) Rahimi, A.; Namyslo,
J. C.; Drafz, M.; Halm, J.; Hübner, E.; Nieger, M.; Rautzenberg, N.;
Schmidt, A. J. Org. Chem. 2011, 76, 7316.
Entry
Reaction conditionsa
pH value
Yield (%)b
1
2
3
4
5
NaOAc
–
16
17
NaOAc, Na2CO3
NaOAc, Na2CO3, H2O, AcOH
NaOAc, H2O
–
5.9
8.3
8.1
68
93
NaOAc, Na2CO3, H2O
>99
aReaction conditions: NaOAc (6.1 mmol), Na2CO3 (4.7 mmol), H2O (2 mL),
AcOH (17 mmol), respectively.
bIsolated yields after chromatography.
Finally, we added N-Boc-O-benzyl-L-tyrosine as optical-
ly pure compound into selected model reactions and mea-
sured the optical rotation after isolation from the reaction
mixtures. No racemization took place under the reaction
conditions applied. Additional investigations along these
lines are under way.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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A.-L. Lücke et al.
Letter
Synlett
(7) Lücke, A.-L.; Wiechmann, S.; Freese, T.; Guan, Z.; Schmidt, A. Z.
Naturforsch., B: J. Chem. Sci 2016, 71, 643.
1,4-dioxane (8 mL) and treated with the catalyst (cat. 1–6, 10
mol%). The mixtures were subjected to ultrasound irradiation
for 5 min and then stirred at r.t. for additional 25 min. Then, the
corresponding boronic acid 6a–h (2 equiv), sodium carbonate
(4.7 mmol), and water (2 mL) were added. The mixtures were
heated at 70 °C for 30 min. After cooling to r.t. the mixtures
were dried over MgSO4. The resulting crude products were
purified by column chromatography over silica gel (40–60
mesh) using a PE-CH2Cl2 (1:3) mixture as eluent. The analytical
data and the characterization of each produced compound can
be found in the Supporting Information.
(8) (a) Gilchrist, T. L. In Science of Synthesis;1V3o.
l
Storr, R. C.; Gilchrist, T.
L., Eds.; Thieme: Stuttgart, 2014, 109. (b) Browne, D. L.; Harrity,
J. P. Tetrahedron 2010, 66, 553. (c) Earl, J. C.; Mackney, A. W.
J. Chem. Soc. 1935, 899.
(9) Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A. Tetrahedron 1985,
41, 2239.
(10) (a) Ollis, W. D.; Ramsden, C. A. Adv. Heterocycl. Chem. 1976, 19,
1. (b) Ramsden, C. A. In Comprehensive Organic Chemistry;
4
V
o.
l
Sammes, P. G., Ed.; Pergamon Press: Oxford, 1979, 1171.
(11) Kato, H.; Ohta, M. Bull. Chem. Soc. Jpn. 1959, 32, 282.
(12) (a) Kalinin, V. N.; She, F. M.; Khandozhko, V. N.; Petrovskii, P. V.
Russ. Chem. Bull. 2001, 50, 525. (b) Kalinin, V.; Fan Min, S.;
Petrovskii, P. J. Organomet. Chem. 1989, 379, 195.
(13) Schmidt, A.; Wiechmann, S.; Freese, T. ARKIVOC 2013, (i), 424.
(14) (a) Wei, K.; Zhang, B.; Ni, J.; Geng, J.; Zhang, J.; Xu, D.; Cui, Y.; Liu,
Y. Inorg. Chem. Commun. 2015, 51, 103. (b) Wang, H.; Wang, J.;
Qiu, W.; Yang, F.; Liu, X.; Tang, J. Chin. J. Chem. 2010, 28, 2416.
(c) Yang, W.; Liu, Q. J. Chem. Commun. 2010, 46, 2659.
(d) Schaarschmidt, D.; Lang, H. ACS Catal. 2011, 1, 411.
(15) Examples for Suzuki–Miyaura reactions without additional
water: (a) Wong, P. Y.; Chow, W. K.; Chung, K. H.; So, C. M.; Lau,
C. P.; Kwong, F. Y. Chem. Commun. 2011, 47, 8328. (b) Bhayana,
B.; Fors, B. P.; Buchwald, S. L. Org. Lett. 2011, 9, 3954.
(16) General Procedure for the Preparation of Compounds 7a–h
Under a nitrogen atmosphere samples of 1-chloro-2,4-dinitro-
benzene (1, 0.050 g, 0.2 mmol) were dissolved in anhydrous
2,4-Dinitro-1,1′:4′,1′′-terphenyl (7f)
A sample of 1-(4-biphenyl)-boronic acid (0.098 g, 0.5 mmol),
cat. 1 (10 mol%), Na2CO3 (4.7 mmol), and AcOH (17 mmol) were
used. The reaction was monitored by TLC. The product was iso-
lated as a yellowish solid; yield 91%; mp 154 °C. 1H NMR (600
MHz, CDCl3): δ = 7.41–7.42 (m, 3 H, H-2′, H-4′, H-6′), 7.47–7.49
(m, 2 H, H-3′′, H-5′′), 7.62–7.64 (d, J = 7.7 Hz, 2 H, H-2′′, H-6′′),
7.69–7.72 (m, 3 H, H-3′, H-5′, H-6′), 8.46–8.48 (dd, J = 7.7 Hz, 1
H, H-5), 8.72 (s, 1 H, H-3) ppm. 13C NMR (150 MHz, CDCl3): δ =
119.7 (+, 1 C, C-3), 126.5 (+, 1 C, C-5), 127.1 (+, 2 C, C-6′′, C-2′′),
127.7 (+, 2 C, C-3′, C-5′), 128.0 (+, 1 C, C-4′′), 128.1 (+, 2 C, C-6′,
C-2′), 128.9 (+, 2 C, C-3′′, C-5′′), 133.1 (+, 1 C, C-6), 133.9 (o, 1 C,
C-1′), 139.7 (o, 1 C, C-1′′), 141.8 (o, 1 C, C-1), 142.4 (o, 1 C, C-4′),
146.8 (o, 1 C, C-4), 149.0 (o, 1 C, C-2) ppm. IR (ATR): ν = 666,
833, 1274, 1489, 1598, 3079 cm–1. MS (EI-MS, 70 eV): m/z
(C18H12N2O4)
= 320.1. HRMS (EI, 70 eV): m/z calcd for
[C18H12N2O4]+: 320.0797; found: 320.0797.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D