Phthalide: A direct building-block towards P,O and P,N hemilabile ligands. Application in the palladium-catalysed Suzuki-Miyaura cross-coupling of aryl chlorides

Article abstract of DOI:10.1039/c3ob40198g

The direct synthesis of new hemilabile ligands from the economical, readily available lactone phthalide is described. Pd-complexes of one such ligand were found highly effective in general Suzuki-Miyaura cross-coupling reactions, including deactivated and hindered aryl chlorides. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40198g

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Phthalide: a direct building-block towards P,O
and P,N hemilabile ligands. Application in the
palladium-catalysed Suzuki–Miyaura cross-coupling
of aryl chlorides†
Cite this: Org. Biomol. Chem., 2013, 11,
2404
Received 29th January 2013,
Accepted 27th February 2013
DOI: 10.1039/c3ob40198g
James McNulty* and Kunal Keskar
www.rsc.org/obc
The direct synthesis of new hemilabile ligands from the econo-
mical, readily available lactone phthalide is described. Pd-com-
plexes of one such ligand were found highly effective in general
Suzuki–Miyaura cross-coupling reactions, including deactivated
and hindered aryl chlorides.
Hemilabile P,O and P,N functionalised ligands1a,b have emer-
ged1a,b and continue to advance as important effectual ligands
with applications to an expanding array of metal catalysed
cross-coupling reactions as well as hydrogenation and cyclo-
addition reactions. The success of hemilabile ligands in filling
methodological gaps in transition metal catalysis has inspired
the development of efficient routes toward new ligand types,
select examples of which are listed in Fig. 1. Guram and co-
workers developed the P,O and P,N-type ligands A and B for
Suzuki–Miyaura cross-coupling of aryl chlorides.1c Kwong and
co-workers introduced the indolylphosphines C1d,e while Pfaltz
and co-workers have extensively utilized phosphine-oxazoline
ligand D in hydrogenation and other processes.1f Stradiotto
and co-workers have introduced similar hemilabile ligands for
aryl chloride amination1g and alkyne hydroamination.1h
Our group has been involved in the design and application
of useful phosphine ligands over the last decade.2 We recently
reported the synthesis and application of the P,O and P,N-type
ligands E and F (Fig. 1) for Suzuki–Miyaura coupling reac-
tions,3 including successful reaction of deactivated, ortho-sub-
stituted aryl chlorides. Silver(I) complexes of the hemilabile
ligand G were demonstrated to be highly effective in promot-
ing the first examples of homogeneous silver catalysed azide–
alkyne cycloaddition reactions.4 An extensive structure–activity
study with ligands of type G revealed the importance of the
hemilabile ligand in promoting the catalytic cycle through
Fig. 1 Hemilabile P,O and P,N type ligands employed in metal-mediated cross-
coupling and other processes.
on-again, off-again polarisation of intermediates.4 The P,O
ligands E are available in only two synthetic steps from com-
modity materials and the P,N ligand F in only one step, invol-
ving free radical addition of a secondary phosphine to 2-vinyl
pyridine. Our criteria are that such ligands should be available
in a few steps from commodity materials and, in view of air-
sensitivity of many phosphines, involve robust conditions in
the preparation, isolation and handling of the ligand. It
occurred to us that the commodity lactone phthalide 1 could
serve as a pivotal building block in the synthesis of new P,N
and/or P,O ligands as homologues of ligand type G, should
opening of the lactone be feasible through treatment with
either a Bronsted or Lewis acid and a secondary phosphine
(Scheme 1). Secondary and tertiary phosphine HBr5 and HBF4
salts6 have proven to be useful air-stable phosphine equiva-
lents. In this paper, we report our success opening this phtha-
lide route toward stable HBr salts of new hemilabile ligands
and application in the Pd-mediated Suzuki–Miyaura cross-
coupling reaction.
Phthalide 1 was observed to readily enter into reaction with
commercial hydrogen bromide (33%) in acetic acid yielding
α-bromo-ortho-toluic acid in good yield without need of purifi-
cation.7 Treatment of the resulting α-bromo-ortho-toluic acid
with ditertiarybutyl phosphine in acetone yielded the car-
boxylic acid functionalised ligand 2 in the form of its air stable
HBr salt in 70% overall isolated yield from 1. For the synthesis
Department of Chemistry and Chemical Biology, McMaster University, Hamilton,
Ontario, Canada, L8S 4M1. E-mail: jmcnult@mcmaster.ca; Fax: (+1)-905-522-2509;
Tel: (+1)-905-525-9140 Ext. 27393
†Electronic supplementary information (ESI) available: General experimental
details, procedures, NMR and MS data for all new compounds. See DOI:
10.1039/c3ob40198g
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available, aryl chlorides are more challenging and individual
cases often require optimised reaction conditions with a par-
ticular ligand and Pd source. In general, sterically hindered,
electron-rich mono- or bidentate phosphines have proved to be
useful in effecting these catalytic cycles.12 The employment of
N-heterocyclic carbene ligands13 and, more recently, the use of
hemilabile P,O and P,N-type ligands,1,3 has proven effective in
Pd-catalysed Suzuki–Miyaura reaction of challenging aryl chlor-
ides. The general utility of ligands 2 and 3a–3d was investigated
employing the Pd-catalysed Suzuki–Miyaura cross-coupling
reaction of chlorobenzene 4a with phenylboronic acid 5a as a
starting point. We screened the carboxylic acid P,O-ligand 2
under a variety of conditions (Table 1). Not surprisingly, choice
of base was observed to be critical with CsF proving optimal,
yielding biphenyl in good yield (76%). Stronger bases (K3PO4,
Et3N, Cs2CO3, NaOtBu) proved ineffective for the coupling reac-
tion giving poor or trace (TLC detectable) conversion
(Table 1).14 These results indicate that the free acid is required
on the ligand and that salts are not effective, perhaps due to
low solubility or aggregation in organic media.
We next surveyed the utility of the amide functionalised
ligand series 3a–3d in the standard reaction varying the
ligand, base and palladium source (Table 2). The air-stable
ligands are introduced into the reaction as their HBr salts and
converted in situ to the free phosphine base through addition
of slight excess of the required base.5,6 Overall, Pd2(dba)3
proved to be a more effective Pd-source than Pd(II) acetate,
while potassium phosphate proved to be the superior base. In
one key control experiment, we determined that addition of
excess ligand was detrimental. For example, a Pd : ligand ratio
of 1 : 0.75 (entry 18, 88% isolated) was employed compared
with a Pd : ligand ratio of 1 : 1.25 (entry 19, 74% isolated).
Direct comparison of the ligand effect (Table 2, entries 7, 18,
20 and 21) demonstrated use of ligand 3c to be most effective.
This reaction went to full conversion and biphenyl 6a was iso-
lated in 96% after column chromatography.
Scheme 1 Synthesis of P,O and P,N-type hemilabile ligands from phthalide 1.
(a) HBr–HOAc 70 °C, then. (b) t-Bu2PH, acetone, reflux, 70%. (c) AlCl3, R1R2NH,
88–94%. (d) PBr3, CH2Cl2, 0 °C, then t-Bu2PH, acetone, reflux, 99%.
of the amide functionalised ligands 3a–3d (Scheme 1) a Lewis
acid catalysed ring opening approach was investigated. Phtha-
lide readily opened with a catalytic amount of aluminium tri-
chloride in the presence of a variety of secondary amines, such
as diethylamine, piperidine and N-methyl-N-benzyl amine,
yielding the desired amides.8 Very hindered amines such as N,
N-diisopropylamine failed to react and an alternative approach
(vide infra) was developed to access ligand 3b. The ring
opening approach yielded the amides 3a, 3c and 3d exclusively
as the primary ortho-benzylic alcohols, providing the handle
for attachment of the phosphine moiety. The alcohols were
converted to their benzylic bromide derivatives quantitatively
with PBr3 in dichloromethane and subsequently reacted with
ditertiarybutyl phosphine in acetone to yield ligands 3a, 3c
and 3d. These ligands are obtained in isolated yields of
between 88–94% from phthalide over this two-step (1 to 3a, 3c
and 3d) sequence.
We previously demonstrated the N,N-diisopropylamide
functionalised hemilabile ligand (Fig. 1, type G) to be most
effective in the Ag-mediated Huisgen reaction.4 In order to
build a comprehensive ligand series for screening purposes,
we developed an alternative process for the synthesis of ligand
3b as shown (Scheme 2). Commercially available N,N-diiso-
propylbenzamide was subjected to directed ortho-lithiation
and formylated with DMF yielding the ortho-aldehyde cleanly.
The formyl derivative was stirred overnight with NaBH4 in
methanol at room temperature to give the benzylic alcohol
intermediate in good yield,9 which was then converted to
ligand 3b quantitatively under the conditions reported above.
The palladium catalysed Suzuki–Miyaura cross-coupling
reaction of aryl halides with aryl-boron derivatives represents a
simple and effective route towards synthesis of substituted
biaryls.10 Biaryl substructures are well represented among
important classes of organic compounds with applications in
pharmaceutical, agrochemical and materials chemistry.11 Aryl
iodides and bromides are the most common halide partners
used in Suzuki cross-coupling reactions. Although more readily
Table 1 Suzuki–Miyaura cross coupling reaction of chlorobenzene with
Pd-complexes of ligand 2
Entry
Base
“Pd”
Solvent
Isolated yield (%)
1
2
3
4
5
6
7
8
K3PO4
K3PO4
K3PO4
CsF
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
PhMe
Dioxane
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
Trace
Trace
52
76
Trace
37
Et3N
Cs2CO3
NaOtBu
K2CO3
13
28
Reaction conditions: 4a (0.040 g, 0.355 mmol, 1.0 equiv.), 5a (0.052 g,
0.426 mmol, 1.2 equiv.), base (1.065 mmol, 3.0 equiv.), Pd(OAc)2
Scheme 2 Synthesis of ligand 3b from N,N-diisopropylbenzamide. (a) s-BuLi
(1.1 equiv.), THF, then DMF (quench). (b) NaBH4, MeOH, 0 °C, 70%. (c) PBr3,
CH2Cl2, 0 °C. (d) t-Bu2PH, acetone, reflux, 99%.
(2.0 mol%) or, Pd2(dba)3 (2.0 mol% (4.0 mol% Pd)), ligand
(3.0 mol%), solvent (2.5 mL), 110 °C.
2
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Table 2 Screening phthalide-derived ligands 3a–3d in the Suzuki–Miyaura
Table 3 Suzuki–Miyaura cross coupling reaction of aryl halides with Pd-com-
plexes of ligand 3c
cross coupling reaction
Isolated
yield (%)
Entry
Base
“Pd”
“L”
Solvent
Isolated yield (%)
Entry Ar–Cl
Ar′–B(OH)2
Product
1
2
3
4
5
6
7
8
Et3N
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3c
3d
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
Dioxane
PhMe
PhMe
PhMe
PhMe
Trace
44
61
76
43
83
87
15
18
55
18
10
Trace
39
33
9
30
1
96
K3PO4
Cs2CO3
CsF
NaOtBu
K2CO3
K3PO4
Cs2CO3
Cs2CO3
K3PO4
K2CO3
Na2CO3
Et3N
2
3
4
5
92
98
90
99
9
10
11
12
13
14
15
16
17
18
19
20
21
CsF
NaOtBu
NaOAc
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
88
74a
96
6
7
90
99
91
Reaction conditions: for entries 1–18, 20–21: 4a (0.040 g, 0.355 mmol,
1.0 equiv.), 5a (0.052 g, 0.426 mmol, 1.2 equiv.), base (1.065 mmol,
3.0 equiv.), Pd(OAc)2 (2.0 mol%) or, Pd2(dba)3 (2.0 mol% (4.0 mol% Pd)),
3a–3d (3.0 mol%), solvent (2.5 mL).a Entry 19: 4a (0.040 g, 0.355 mmol,
1.0 equiv.), 5a (0.052 g, 0.426 mmol, 1.2 equiv.), base (1.065 mmol,
3.0 equiv.), Pd2(dba)3 (2.0 mol% (4.0 mol% Pd)), 3a–3d (5.0 mol%),
solvent (2.5 mL), 110 °C.
8
90
90
83
9
The overall optimised reaction condition identified from
this screen was selected in order to probe the efficiency of
Pd-complexes of ligand 3c in the general Suzuki–Miyaura reac-
tion with more challenging aryl chlorides. Overall, palladium
complexes of ligand 3c proved to have broad substrate scope,
the overall results of this investigation are presented in
Table 3. The standard reaction condition was employed and
no attempt was made to optimise individual entries in Table 3.
Electron rich and sterically hindered aryl chlorides under-
went efficient cross-coupling with various aryl boronic acids
leading to high isolated yield of biaryls (83–99%). Activated
(electron deficient) aryl chlorides (Table 3, entry 5, 7) expect-
edly gave excellent yields (99%) with phenyl boronic acid. The
electron deficient 4-acetylphenylboronic acid also underwent
10
11
85
General reaction conditions: aryl chloride (0.040 g, 0.355 mmol,
1.0 equiv.), aryl boronic acid (0.052 g, 0.426 mmol, 1.2 equiv.),
K3PO4 (0.226 g, 1.065 mmol, 3.0 equiv.), Pd2(dba)3 (6.5 mg, 2.0 mol%),
ligand 3c (4.5 mg, 3.0 mol%), PhMe (2.5 mL), 110 °C.
clean coupling with chlorobenzene giving 90% isolated yield rapid construction of new hemilabile phosphine ligands. In
(Table 3, entry 6). particular, Pd-complexes of the piperidinamide ligand 3c
Most gratifying were the results observed with deactivated proved to be highly effective in the Suzuki–Miyaura cross-coup-
(methyl and methoxy substituted) and sterically hindered ling reaction of activated, deactivated as well as sterically hin-
ortho-substituted aryl chlorides (Table 3, entries 8–11). These dered aryl chlorides. The cost and air-sensitivity of many
substrates were observed to proceed to high conversion with hemilabile ligands currently employed present economical
Pd-complexes of ligand 3c, and the corresponding biaryls were and technical challenges. Ligand 3c is readily available in two
isolated in high (83–90%) overall yield.
steps from phthalide and directly produced as its air stable
In conclusion, we have shown the economical, readily avail- HBr salt, allowing easy isolation, storage and handling. Many
able lactone phthalide to be a useful building block for the variations of the chemistry disclosed can be considered to
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