Highly efficient carbazolyl-derived phosphine ligands: Application to sterically hindered biaryl couplings

Article abstract of DOI:10.1039/c1cc10708a

A new family of phosphine ligands bearing a bulky carbazolyl scaffold is described. With the combination of ligand 2a and Pd(OAc)₂, difficult tri-ortho-substituted biaryl couplings are accomplished smoothly. In particular, the catalyst loading as low as 0.02 mol% of Pd for non-activated 2,6-disubstituted aryl chloride coupling can be achieved.

Full text of DOI:10.1039/c1cc10708a

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COMMUNICATION
Highly efficient carbazolyl-derived phosphine ligands: application
to sterically hindered biaryl couplingsw
Sheung Chun To and Fuk Yee Kwong*
Received 6th February 2011, Accepted 10th March 2011
DOI: 10.1039/c1cc10708a
A new family of phosphine ligands bearing a bulky carbazolyl
scaffold is described. With the combination of ligand 2a and
Pd(OAc)2, difficult tri-ortho-substituted biaryl couplings are
accomplished smoothly. In particular, the catalyst loading as
low as 0.02 mol% of Pd for non-activated 2,6-disubstituted aryl
chloride coupling can be achieved.
Fig. 1 Previous ligand structures/coordinations and our present
attempted investigation.
Palladium-catalyzed cross-coupling reactions have been successful
in constructing various aromatic carbon–carbon bonds.1 In
particular, Suzuki–Miyaura coupling has captured considerable
attention in a variety of material and pharmaceutical inter-
mediate syntheses.2 In fact, a plethora of evolutional phosphine
ligands have been designed to give milder coupling reaction
conditions, as well as vastly expand the substrate scope
for these reactions. For instance, Buchwald’s biaryl-based
monophosphines3 and Beller’s heterobiaryl phosphines4 have
been shown as excellent phosphine ligands for palladium-
catalyzed aromatic carbon–carbon and carbon–heteroatom
bond-forming processes. Interestingly, even though these biaryl-
type monophosphines are generally regarded as monodentate
ligands, the X-ray crystallographic data unambiguously
showed that the non-phosphine containing arene ring binds
to the palladium center to a certain extent (via ipso-carbon
coordination).5 This coordination has been suggested as a key
feature to enhance the oxidative addition step in cross-coupling
reactions.6
vancomycin,9 steganacin10 and an a2/3-selective GABAA agonist
candidate.11 In view of this difficult but valuable method, we
are attracted to explore a ligand structure which can effectively
handle the sterically congested coupling reaction from aryl
chlorides. Herein, we report a new series of carbazolyl-derived
phosphine ligands and their applications in sterically hindered
tri-ortho-substituted biaryl synthesis, using low palladium
loading.
Inspired by the interesting ipso-carbon-Pd coordination12
and Stradiotto’s morpholinyl P,N-type ligand structure13
(with a flexible bottom ring and sp3-N-Pd coordination)
(Fig. 1), we were interested in exploring carbazolyl ligands
with all-aromaticity in the heteroaromatic ligand scaffold. The
flattened carbazolyl bottom ring takes advantage to provide
an extended flat-wall-like rigidity for facilitating the reductive
elimination process, while the sp2-N would offer a weak
coordination to the palladium center whenever needed during
the catalytic cycle to potentially increase the catalyst longevity.
We embarked to prepare the carbazolyl-derived ligand
series by using the Cu-catalyzed C–N bond coupling of
1,2-dibromobenzene and carbazole (Scheme 1).14 In our ligand
synthesis optimization, Cu2O salt was found to be more
effective than CuI in this N-arylation. The single X-ray crystal
structure was obtained from the reaction of PdCl2(CH3CN)2
and 2a (Fig. 2). The palladium dimer complex showed that the
two ligands were trans to each other. The proximity of the
Numerous phosphines are found to be effective in the Suzuki–
Miyaura coupling reaction. The effectiveness of these ligands
is usually screened by the model reaction with sterically
non-hindered coupling partners. The sterically encumbered
tri-ortho-substituted biaryl examples are not always reported
in general using stated reaction conditions, but usually require
higher catalyst loading or elevated reaction temperature.7 To
the best of our knowledge, there have been only a few reports
disclosing the general tri-ortho-substituted biaryl synthesis
from aryl chlorides, especially in using low Pd loading.8 In
fact, there are many pharmaceutically attractive organic
molecules bearing tri-ortho-substituted biaryl motifs, such as
State Key Laboratory of Chirosciences and Department of Applied
Biology and Chemical Technology, The Hong Kong Polytechnic
University, Kowloon, Hong Kong. E-mail: bcfyk@inet.polyu.edu.hk
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc10708a
Scheme 1 The synthesis of carbazolyl-derived phosphines.
Chem. Commun., 2011, 47, 5079–5081 5079
c
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Table 2 Palladium-catalyzed Suzuki–Miyaura coupling of di-ortho-
substituted aryl chloridesa
Pd
%
Entry Ar0Cl
Ar0B(OH)2 Product
loading Yieldb
1
2
0.02% 98
0.02% 96
3
4
5
0.1% 86
0.2% 99
0.2% 70
Fig. 2 ORTEP drawing of the Pd–2a complex.
Table 1 An evaluation of carbazolyl-derived phosphine ligands 2a
6
0.1% 82
0.1% 86
0.2% 95
0.1% 76
Entry
Ligand 2
Base
Solvent
Yield%b
7
1
2
3
4
5
2a
2b
2c
2d
2e
K3PO4ꢀH2O
K3PO4ꢀH2O
K3PO4ꢀH2O
K3PO4ꢀH2O
K3PO4ꢀH2O
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
98 (95)c
20
89
11
9
a
8
Reaction conditions: Pd(OAc)2 (0.02 mol%), ligand 2 (0.06 mol%),
ArCl (1.0 mmol), Ar0B(OH)2 (1.5 mmol), PhB(OH)2 (1 mg), base
(3.0 mmol), solvent (3.0 mL) were stirred for 24 h at 110 1C under
b
c
nitrogen. Calibrated GC yields were reported. Isolated yield in
parenthesis.
9
nitrogen atom on the carbazole ring to the palladium center
was 3.3 A. The stiff and bulky carbazole plane hindered one
side of the palladium complex.
To test the effectiveness of the new family of ligand, we
avoided the use of ‘‘privileged’’ phenylboronic acid as the
nucleophile. Thus, difficult 2-chloro-m-xylene and 2-tolylboronic
acid were chosen in our model investigations (Table 1). Ligand
2a and 2c bearing Cy and iPr groups, respectively, gave
superior results (entries 1 and 3). It is noteworthy that this
tri-ortho-substituted biaryl coupling is highly sensitive to the
steric bulkiness of the ligand. The incorporation of the sterically
more hindered –PtBu2 group or sterically less congested –PEt2
group to the ligand scaffold (2b and 2d, respectively) provided
significantly inferior results (entries 2 and 4). The ligand 2e
with the –PPh2 moiety gave 9% yield (entry 5). Solvents and
bases were screened (see ESIw).
10
0.2% 99
0.1% 85
11
a
Reaction conditions: ArCl (1.0 mmol), ArB(OH)2 (1.5 mmol),
Pd(OAc)2 (mol% as indicated), ligand (Pd/2a, 1 : 3), PhB(OH)2
(1 mg), K3PO4ꢀH2O (3.0 mmol), dioxane (3.0 mL) were stirred for
24 h (reaction time for each substrate is not optimized) at 110 1C under
b
nitrogen. Isolated yields.
With the optimized reaction conditions in hand, we next
probed the substrate scope of this new catalyst system (Table 2).
The coupling of sterically more hindered 2-ethylphenylboronic
acid with 2-chloro-m-xylene was successfully achieved using
0.02 mol% of palladium loading (entry 2). This represents the
lowest catalyst loading achieved so far for tri-ortho-substituted
biaryl synthesis where the ortho-substituted group is bigger
than a methyl moiety. In general, the tri-ortho-substituted
biaryl syntheses could be accomplished within the range of
0.02–0.2 mol% of catalyst. Functional groups such as nitro,
cyano, ester, etc. were well tolerated (Table 2). In particular
the even more challenging substrate, both deactivated and
sterically hindered aryl chloride, could be successfully coupled
(entry 7).
The newly developed catalyst system was further extended to
the coupling of anthracene derivatives (Table 3). 9-Chloro-
anthracene was coupled with a series of ortho-substituted aryl-
boronic acids in excellent yields (entries 1–4). Acridine was also a
feasible coupling partner (entries 6–7). The aldehyde group was
compatible under these reaction conditions (entry 10).
c
5080 Chem. Commun., 2011, 47, 5079–5081
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Table 3 Palladium-catalyzed Suzuki–Miyaura coupling of anthracene-
based aryl chloridesa
Notes and references
1 (a) A. de Meijere, in Metal-Catalyzed Cross-Coupling Reactions,
ed. F. Diederich, Wiley-VCH, Weinheim, 2nd edn, 2004, vol. 1–2;
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Wiley-Interscience, 2002, vol. 1–2; (c) J.-P. Corbet and G. Mignani,
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Modern Arylation Methods, Wiley-VCH, Weinheim, 2009.
2 (a) A. O. King and N. Yasuda, in Organometallics in Process
Chemistry, ed. R. D. Larsen, Springer-Verlag, Berlin, Heidelberg,
2004, pp. 205–245; (b) K. C. Nicolaou, P. G. Bulger and D. Sarlah,
Angew. Chem., Int. Ed., 2005, 44, 4442.
Pd
%
Entry ArCl
Ar0B(OH)2 Product
loading Yieldb
1
2
3
4
0.05% 97
0.1% 98
0.1% 84
0.05% 98
3 For an account, see: R. Martin and S. L. Buchwald, Acc. Chem.
Res., 2008, 41, 1461 and references therein.
4 For a review, see: A. Zapf and M. Beller, Chem. Commun., 2005,
431 and references therein.
5
0.1% 95
5 (a) J. Yin, M. P. Rainka, X. X. Zhang and S. L. Buchwald, J. Am.
Chem. Soc., 2002, 124, 1162; (b) R. Pratrap, D. Parrish, P. Gunda,
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6 (a) T. E. Barder and S. L. Buchwald, J. Am. Chem. Soc., 2007, 129,
12003; (b) T. E. Barder, M. R. Biscoe and S. L. Buchwald,
Organometallics, 2007, 26, 2183; (c) Z. Weng, S. Teo and
A. T. S. Hor, Acc. Chem. Res., 2007, 40, 676.
6
7
0.1% 92
0.1% 92
8
0.1%
94
7 (a) K. Billingsley, K. W. Anderson and S. L. Buchwald, Angew.
Chem., Int. Ed., 2006, 45, 3484; (b) H. Ohta, M. Tokunaga,
Y. Obora, T. Iwai, T. Iwasawa, T. Fujihara and Y. Tsuji, Org.
Lett., 2007, 9, 89; (c) W. Dai, Y. Li, Y. Zhang, C. Yue and J. Wu,
Chem.–Eur. J., 2008, 14, 5538; (d) S. Doherty, J. G. Knight,
C. H. Smyth and G. A. Jergenson, Adv. Synth. Catal., 2008, 350,
1801; (e) K. Sawai, R. Tatumi, T. Nakahodo and H. Fujihara,
Angew. Chem., Int. Ed., 2008, 47, 6917; (f) D. Lee, M. Choi, B. Yu,
R. Ryoo, A. Taher, S. Hossain and M. Jin, Adv. Synth. Catal.,
2009, 351, 2912; (g) L. Ackermann, H. K. Patukuchi,
A. Althammer, R. Born and P. Mayer, Org. Lett., 2010, 12,
1004; (h) X. Shen, G. O. Jones, D. A. Watson, B. Bhayana and
S. L. Buchwald, J. Am. Chem. Soc., 2010, 132, 11278;
(i) S. Doherty, J. G. Knight, J. P. McGrady, A. M. Ferguson,
N. A. B. Ward, R. W. Harrington and W. Clegg, Adv. Synth.
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Chem. Soc., 2000, 122, 4020; (k) J. K. Jensen and M. Johannsen,
Org. Lett., 2003, 5, 3025.
8 (a) T. E. Barder, S. D. Walker, J. R. Martinelli and S. L. Buchwald,
J. Am. Chem. Soc., 2005, 127, 4685; (b) T. Hoshi, T. Nakazawa,
I. Saitoh, A. Mori, T. Suzuki, J. Sakai and H. Hagiwara, Org. Lett.,
2008, 10, 2063; (c) T. Hoshi, I. Saitoh, T. Nakazawa, T. Suzuki,
J. Sakai and H. Hagiwara, J. Org. Chem., 2009, 74, 4013; (d) C. M. So,
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Lett., 2011, 13, 252.
9
0.1% 91
0.1% 90
10
a
Reaction conditions: ArCl (1.0 mmol), ArB(OH)2 (1.5 mmol),
Pd(OAc)2 (mol% as indicated), ligand (Pd/2a, 1 : 3), PhB(OH)2 (1 mg),
K3PO4ꢀH2O (3.0 mmol), dioxane (3.0 mL) were stirred for 24 h at 110 1C
b
under N2. Isolated yields.
The palladium-catalyzed coupling of 2,6-disubstituted aryl-
boronic acids with hindered aryl chlorides was feasible
(see ESI Tablew). Chloropyridine and chlorothiophene
coupled with 2-m-xylylboronic acid smoothly (entries 4–5).
In general, the coupling of sterically hindered arylboronic acid
leading to the same tri-ortho-substituted biaryl requires higher
catalyst loading (cf. ESI Tablew, entry 1 vs. Table 2, entry 1).
Presumably the transmetallation of the bulky organoboron
nucleophile is not efficient.
In summary, we have reported a new family of highly
effective carbazolyl-derived phosphine ligands. We found that
the tri-ortho-substituted biaryl coupling is highly sensitive to
the ligand bulkiness. Ligands bearing either the more hindered
–PtBu2 group or less hindered –PEt2 moiety did not benefit to
the reaction, while moderate bulkiness –PCy2 and –PiPr2
groups favored this catalysis. This information may provide
an important note for future ligand design aimed towards
challenging and difficult coupling processes. With the aid of
the new Pd–2a complex, a general system for tri-ortho-substituted
biaryl synthesis is established and particularly noteworthy is
that the catalyst loading can be as low as 0.02 mol% Pd for
non-activated aryl chlorides. We believe these new ligand
systems are highly versatile for handling other difficult coupling
reactions.
9 K. C. Nicolaou, C. N. C. Boddy, S. Brase and N. Winssinger,
Angew. Chem., Int. Ed., 1999, 38, 2096.
10 O. Baudoin and F. Gueritte, in Studies in Natural Product
Chemistry, ed. A.-U. Rahman, Elsevier, Amsterdam, 2003, vol.
29, pp. 355–418.
11 For example from Merck, see: D. R. Gauthier Jr., J. Limanto,
P. N. Devine, R. A. Desmond, Jr., R. H. Szumigala, B. S. Foster
and R. P. Volante, J. Org. Chem., 2005, 70, 5938.
12 For S-Phos, see: (a) T. E. Barder, S. D. Walker, J. R. Martinelli
and S. L. Buchwald, Angew. Chem., Int. Ed., 2004, 43, 1871; For
MAP type ligand, see: (b) P. Kocovsky´ , S. Vyskocil, I. Cisarova,
J. Sejbal, I. Tislerova M. Smrcina, G. C. Lloyd-Jones,
´
,
S. C. Stephen, C. P. Butts, M. Murray and V. Langer, J. Am.
Chem. Soc., 1999, 121, 7714.
We thank the Research Grants Council of Hong Kong
(GRF: PolyU5014/10P) and PolyU Internal Grant (A-PG13)
for support. UGC special equipment grant (SEG PolyU01) is
acknowledged. Prof. Z. Zhou is thanked for X-ray support.
13 R. J. Lundren, B. D. Peters, P. G. Alsabeh and M. Stradiotto,
Angew. Chem., Int. Ed., 2010, 49, 4071.
14 J. C. Antilla, A. Klapars and S. L. Buchwald, J. Am. Chem. Soc.,
2002, 124, 11684.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5079–5081 5081