Practical: In situ -generation of phosphinite ligands for palladium-catalyzed carbonylation of (hetero)aryl bromides forming esters

Article abstract of DOI:10.1039/c7cc02828h

An effective method for alkoxycarbonylation of (hetero)aryl bromides is developed in the presence of in situ-generated phosphinite ligands ^tBu₂POR (R = ⁿBu, ⁿPr, Et or Me). For this purpose commercially available ^tBu₂PCl was used as the pre-ligand in the presence of different alcohols. For the first time cross coupling reactions with two alcohols-one generating the ligand, the other used as substrate-were developed. Through this method, ligand optimization can be performed in a more efficient manner and the desired products could be obtained with good yields and selectivity.

Full text of DOI:10.1039/c7cc02828h

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: L. Wang, H.
Neumann, A. Spannenberg and M. Beller, Chem. Commun., 2017, DOI: 10.1039/C7CC02828H.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Volume 52 Number
1 4 January 2016 Pages 1–216
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C7CC02828H
Journal Name
COMMUNICATION
Practical In-situ-generation of Phosphinite Ligands
for Palladium-catalyzed Carbonylation of
Received 00th January 20xx,
Accepted 00th January 20xx
(Hetero)aryl Bromides Forming Esters
Lin Wang, Helfried Neumann, Anke Spannenberg, Matthias Beller*
DOI: 10.1039/x0xx00000x
www.rsc.org/
6
An effective method for alkoxycarbonylation of (hetero)aryl optimizing a given transformation. Thus, there exist a significant
bromides is developed in the presence of in-situ-generated potential to replace phosphines by phosphinites in several
phosphinite ligands tBu2POR (R = nBu, nPr, Et or Me). For this transition metal catalyzed reactions.7
purpose commercially available tBu2PCl was used as the pre-ligand
Palladium-catalyzed alkoxycarbonylation of aryl halides is an
in the presence of different alcohols. For the first time cross effective and important method to produce aromatic carboxylic
8
coupling reactions with two alcohols – one generating the ligand, acid derivatives. Generally, the ligands suitable for this reaction
the other used as substrate - were developed. Through this are monodentate (BuPAd2, PtBu3, PCy3) or bidentate phosphines
method, ligand optimization can be performed in a more efficient (dppf-, Xantphos-, BINAP-ligands) with often strong electronic
manner and the desired products could be obtained with good donor abilities.9 Clearly, some of these phosphine ligands are as or
yields and selectivity.
more expensive compared to metal. Therefore, alternative ligands
lower in price with similar reactivity are worth being explored.
Based on our previous experience in coupling reactions, we had the
idea that phosphinite ligands with two bulky groups and a small
fragment may meet this requirement.
The activity and selectivity of a given catalyst is determined to a
large extent by the surrounding microenvironment.1 In this respect,
the development of improved practical organometallic catalysts
requires the use of inexpensive and available ligands. While
currently an enormous scientific interest focuses on the use of
abundant metals 2, much less interest is concerned with the use
“economical” ligands. Until today, the most important class of
ligands constitutes phosphines, which are sometimes tedious to
prepare, expensive and sensitive to air.3 In contrast, phosphinite
ligands, which contain one P-O bond and two P-C bonds, are easier
to synthesize from various commercially available R2P-X derivatives.
An additional attractive feature of these P-compounds (R’R’’POR, R,
R’ and R’’ = alkyl or aryl group) is their special electronic and
topological effect controlled by the -OR group.4 In general, they are
produced under mild conditions from R’R’’PCl with alcohols in the
Herein, we report a convenient and effective method for
alkoxycarbonylation of (hetero)aryl bromides in the presence of
various phosphinite ligands tBu2POR (R = nBu, nPr, Et or Me).
Compared to most previous works, in this method the ligand is
generated in situ (Scheme 1).
Previous work:
O
cataCXiumA, Pd(OAc)2,
nBuOH, base, CO
Br
O
R
R
This work:
R
O
O
t
1. Bu2PCl, R'OH, base
R'
presence
of
base
such
as
Et3N,
N,N,N’,N’-
Br
Br
O
O
2. Pd(OAc)2, arylbromide, CO
tetramethylethylenediamine (TMEDA), sodium or nBuLi.5 By using
structurally diverse alcohols, phosphinites with different electronic
nature, steric hindrance, solubility and other properties could be
conveniently obtained. Furthermore, it should be feasible to
prepare such ligands through an in situ protocol, which will be a
powerful tool for easily generating numerous ligands and thus
R
R
or
t
1. Bu2PCl, R'OH, base
R''
2. Pd(OAc)2, arylbromide, R''OH, CO
R
Scheme 1 Phosphinites generated in situ to catalyze the alkoxycarbonylation
of (hetero)aryl bromides
Initially, a series of phosphinite ligands tBu2POR [R = n-propyl
(L1), n-butyl (L2), i-propyl (L3), 2-pyridinylmethyl (L4) and (6-methyl-
2-pyridinyl)methyl (L5)] were synthesized and tested in the
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
View Article Online
DOI: 10.1039/C7CC02828H
COMMUNICATION
Journal Name
alkoxycarbonylation of 4-bromoanisole with n-butanol and TMEDA aryl bromide underwent smooth carbonylation and led to the
as base (Table 1). While ligands L1 and L2 showed similar reactivity corresponding esters in 67-80% (Table 2, 1j – 1l). Encouraged by all
due to the parallel structures and properties (Table 1, entries 1 and these results, we extended this protocol to alkoxycarbonylations
2), the larger steric hindrance of L3 – L5 caused negative impact on with other linear aliphatic alcohols. As shown in Table 3, simply
the reaction (Table 1, entries 3-5). Changing the base to Et3N or 1,8- changing the alcohol gave 13 different methyl, ethyl and n-propyl
Diazabicyclo[5.4.0]undec-7-ene (DBU) improved conversions and (hetero)aromatic esters in high yields (72-94%). Furthermore, a
yields (Table 1, entries 7-8). Next, we generated L2 directly from scale-up experiment for propoxycarbonylation of 4-bromoanisole
butanol (solvent and reactant) with tBu2PCl (1.5 mol%) under has been explored which results in the yield of 96% (Table 3, 4a).
catalytic conditions.10 As a result, the product was obtained in 50%
Esters of sterically crowded alcohols constitute valuable
intermediates for flavor and fragrances. Furthermore, they are
11
yield (Table 1, entry 9), which indicated no complete formation of
the phosphinite ligand. Based on monitoring the transformation of
frequently employed in organic synthesis, e.g. natural product
12
t
tBu2PCl to Bu2POnBu via 31P{1H} NMR (Figure S1), improved “one-
synthesis.
In this respect, we were interested in the
pot” conditions with a pre-reaction of tBu2PCl with butanol and DBU
for 5 h were established. To our delight, the conversion and yield
increased to 100% and 98%, respectively (Table 1, entry 10). It is
alkoxycarbonylation of less reactive, hindered alcohols.
Unfortunately, reaction of 4-bromoanisole with isopropanol as a
model system only led to a conversion up to 35%, even when the
ligand pre-formation was carried out at 80 oC for 24 h (Table 3, 5a).
Investigating this reaction by 31P {1H} NMR spectroscopy (see ESI†,
Fig. S2), we observed that the generation of tBu2POiPr was very
difficult. In order to solve this limitation, we developed a so-called
cross-in-situ protocol. Namely, a combination of two alcohols was
employed.
t
worth mentioning that Bu2PCl cannot be simply replaced by tert-
butyldichloro-phosphine (tBuPCl2), phosphorus trichloride (PCl3) and
chlorodiphenylphosphine (Ph2PCl) (see ESI†: Table S1).
Next, we investigated the scope and limitation of our in situ
protocol. As shown in Table 2, sterically unhindered and electronic-
rich aryl bromides gave high yields of the corresponding ester in the
range of 84-86% (Table 2, 1b – 1d).
Table 2 Butoxycarbonylation of different (hetero)aryl bromides.a
Table 1 Butoxycarbonylation of 4-bromoanisole in the presence of different
ligands and base.a
0.5 mol% Pd(OAc)2
1.5 mol% ligand
Base
O
Br
H
O
+
O
O
20 bar CO
115 oC, 18 h
O
1a
P
O
P
O
P
O
N
P
O
P
O
N
L4
L2
L3
L1
L5
Entry
Ligand
Base
Base
Conversion
[%]b
Yield 1a
[%]b
53
Equivalent
0.75
0.75
0.75
0.75
0.75
0,60
1.5
1
2
L1
L2
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
NEt3
58
57
54
3
L3
48
43
4
L4
45
39
5
L5
35
30
6
L2
40
39
7
L2
82
76
8
L2
tBu2PCl
tBu2PCl
DBU
1.5
94
88
a
Reaction conditions: 1. tBu2PCl (0.03 mmol), n-butanol (2 mL), DBU (3
9
10c
DBU
1.5
53
50
mmol), R.T., 5 h; 2. Pd(OAc)2 (0.01 mmol), (hetero)aryl bromide (2 mmol),
CO (20 bar), 115 oC, 18 h. b Isolated yield. c Reaction temperature: 125 oC.
DBU
1.5
100
98
a Reaction conditions: 4-bromoanisole (2 mmol), n-butanol (2 mL), Pd(OAc)2
(0.01 mmol), ligand (0.03 mmol), base, CO (20 bar), 115 oC, 18 h; TMEDA =
N,N,N’,N’-tetramethylethylenediamine; DBU = 1,8-diazabicyclo[5.4.0]undec-
7-ene. b Determined by GC, hexadecane as the internal standard. c Reaction
conditions: 1. tBu2PCl (0.03 mmol), n-butanol (2 mL), DBU (3 mmol), R.T., 5
h; 2. Pd(OAc)2 (0.01 mmol), 4-bromoanisole (2 mmol), CO (20 bar), 115 oC,
18 h.
A more reactive linear alcohol was used in catalytic amounts to
form the respective ligand in situ, while at the same time an excess
of the sterically hindered alcohol was present to form the desired
product. To establish an active ligand four linear alcohols were
tested and among them n-propanol gave the best yield (85%; Table
4, entries 1-5). Interestingly, under these conditions the
esterification of the less reactive alcohol preceded highly selective
(97%).
Meanwhile, heteroaryl bromides could be transformed to the
desired products in good yields (Table 2, 1e and 1f). Similarly,
electron-withdrawing groups are well tolerated affording 4-chloro-,
4-cyano-, and 4-trifluoromethyl-substituted butyl benzoate in 78-
83% yield (Table 2, 1g – 1i). Notably, even more sterically hindered
From a synthetic viewpoint, it is important that not only
reactions of isopropanol with (hetero)aryl bromides led to good
2 | J. Name., 2017, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 4
View Article Online
DOI: 10.1039/C7CC02828H
Journal Name
COMMUNICATION
yields (Table 5, 5b – 5d), but also alkoxycarbonylations of various
From all these results it becomes clear that in-situ-generated
sterically hindered alcohols went smoothly (Table 5, 6 - 10). In tBu2POnBu performed at least similar to the more expensive
general such esterifications require the addition of special coupling Ad2PnBu ligand. In order to understand this behavior, we
reagents or more harsh conditions.13 To the best of our knowledge investigated key intermediates of the generally accepted catalytic
several of the products shown in Table 5 are synthesized for the cycle. Firstly, Pd(tBu2POnBu)2 was prepared from reaction of
first time via Pd-catalyzed alkoxycarbonylation. Meanwhile, also Pd(allyl)(Cp) with in-situ-generated phosphinite L2. Subsequently,
heteroaryl-substituted alcohols and diols gave the corresponding complex 15 was obtained via oxidative addition of 4-bromoanisole
esters 11-14 in moderate to high yields. In the latter case, mono- to Pd(tBu2POnBu)2 in 52% yield (Scheme 2). NMR (31P, 1H, 13C)
and di-esterification could be easily controlled by the amount of investigations and X-ray diffraction analysis confirmed the dimeric
glycol.
nature of 15. Compared to the known [Pd(Ar)(Br)(Ad2PnBu)]2
complex,14 15 maintained stable in solution, which was proven by
the singlet in 31P{1H} NMR spectrum (156,7 ppm). Interestingly,
comparing the palladium complex 15 and Pd(tBu2POnBu)2, the
signals of α-methylene protons (2.94 ppm) of the butoxy ligand are
strongly shifted up by 1.26 ppm towards higher field (see ESI†:
Table S4), which is explained by the close influence of the aromatic
ring of the substrate.
Table 3 Alkoxycarbonylation of different (hetero)aryl bromides with
different alcohols.a
Table 5. Application scope of cross-in-situ protocol for alkoxycarbonylation.a
O
O
O
8, 60% d, e
a Reaction conditions: 1. tBu2PCl (0.03 mmol), alcohol (2 mL), DBU (3 mmol),
R.T., 5 h; 2. Pd(OAc)2 (0.01 mmol), (hetero)aryl bromide (2 mmol), CO (20
b
c
d
bar), 115 oC, 18 h. Isolated yield. Reaction temperature: 125 oC. Pre-
reaction performed at 80 oC for 24 h. Reaction conditions: 1. Bu2PCl (0.3
mmol), n-propanol (10 mL), DBU (30 mmol), R.T., 5 h; 2. Pd(OAc)2 (0.1
mmol), 4-bromoanisole (20 mmol), CO (20 bar), 115 oC, 18 h.
e
t
Table 4 Cross-in-situ protocol for the isopropoxycarbonylation.a
a Reaction conditions: 1. tBu2PCl (0.03 mmol), n-propanol (10 µL), DBU (3
mmol), R.T., 5 h; 2. Pd(OAc)2 (0.01 mmol), Aryl Bromide (2 mmol), R’’OH (2
mL), CO (20 bar), 115 oC, 18 h. b Isolated yield. c Reaction temperature: 125
oC. d Reaction conditions: 1. tBu2PCl (0.03 mmol), n-proponal (10 µL), DBU (3
mmol), R.T., 5 h; 2. Pd(OAc)2 (0.01 mmol), 4-bromoanisole (3 mmol), R’’OH
(2 mmol), 1,4-dioxane (1.6 mL), CO (20 bar), 125 oC, 20 h. e Isolated yield,
according to the conversion of alcohol. f Reaction conditions: 1. tBu2PCl (0.03
mmol), n-propanol (10 µL), DBU (3 mmol), R.T., 5 h; 2. Pd(OAc)2 (0.01 mmol),
4-bromoanisole (2 mmol), R’’OH (4.0 mmol), 1,4-dioxane (1.6 mL), CO (20
bar), 115 oC, 20 h. [g] Glycol (1.2 mmol) solved in 1,4-dioxane (1.6 mL) was
added.
Volume
(µL)
Conv.
(%) b
Yield 5a
Selectivity
(%) c
Entry
R’OH
(%) b
1
2
3
4
5
MeOH
EtOH
10.0
10.0
10.0
10.0
2.3
83
86
88
87
54
74
78
85 (85)
83
89
91
97
95
98
nPrOH
nBuOH
nPrOH
53
a Reaction conditions: 1. tBu2PCl (0.03 mmol), R’OH, DBU (3 mmol), R.T., 5 h;
2. Pd(OAc)2 (0.01 mmol), 4-bromoanisole (2 mmol), isopropanol (2 mL), CO
(20 bar), 115 oC, 18 h. b Determined by GC, hexadecane as the internal
standard. Isolated yield in parenthesis. c The ratio of yield with conversion.
To demonstrate that complex 15 is a key intermediate in
catalytic cycle, the benchmark coupling reaction was performed in
the presence of 15 as catalyst. Indeed, the ester product was
obtained in 85% yield (Scheme 2).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2017, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
View Article Online
DOI: 10.1039/C7CC02828H
COMMUNICATION
Journal Name
4 | J. Name., 2017, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx