Microwave-promoted palladium(II)-catalyzed C-P bond formation by using arylboronic acids or aryltrifluoroborates

Article abstract of DOI:10.1002/chem.200901473

The first Pd^II-catalyzed P arylation has been performed by using palladium acetate, the rigid bidentate ligand dmphen (dmphen=2,9-dimethyl-1,10- phenanthroline), and without the addition of base or acid. Couplings of arylboronic acids or aryl t

Full text of DOI:10.1002/chem.200901473

FULL PAPER
DOI: 10.1002/chem.200901473
À
Microwave-Promoted Palladium(II)-Catalyzed C P Bond Formation by
Using Arylboronic Acids or ryltrifluoroborates
AHCTUNGTRENNUNG
Mounir Andaloussi,[a] Jonas Lindh,[a] Jonas Sꢀvmarker,[a] Per J. R. Sjçberg,[b] and
Mats Larhed*[a]
Dedicated to Dr. Gunnar Lindeberg on the occasion of his 70th birthday
Abstract: The first PdII-catalyzed
arylation has been performed by using
P
under non-inert conditions. Aryl phos-
phites were also synthesized at room
temperature with atmospheric air as
the sole reoxidant. The arylated phos-
phonates were isolated in 44–90%
yields. The excellent chemoselectivity
of the method was illustrated in the
synthesis of a Mycobacterium tubercu-
losis glutamine synthetase (MTB-GS)
inhibitor. Online ESIMS was used to
detect cationic palladium species in on-
going reactions directly, and a catalytic
cycle has been proposed based on
these results.
ACHTUNGTRENNUNG
palladium acetate, the rigid bidentate
ligand dmphen (dmphen=2,9-dimeth-
yl-1,10-phenanthroline), and without
the addition of base or acid. Couplings
of arylboronic acids or aryl trifluorobo-
rates with H-phosphonate dialkyl
esters were conducted in 30 min with
controlled microwave (MW) heating
Keywords: boronic acids · micro-
wave chemistry · palladium · P ary-
lation · trifluoroborates
Introduction
become widely used in organic chemistry.[8] As a conse-
quence of this advancement, a number of MW-assisted pro-
0
À
During the years prior to 1980 few important new methods
tocols for Pd -catalyzed C P bond formation can be found
for the generation of C P bonds appeared, and the principal
in the literature.[6,9]
À
method available was the Michaelis–Arbuzov reaction.
Starting with the pioneering work of Hirao[1,2] on Pd0-cata-
lyzed couplings of aryl and vinyl bromides with dialkyl phos-
phites, vastly improved methods arose.[3] Owing to the grow-
ing interest in aryl and vinyl phosphonates in medicinal[4]
and polymer chemistry,[5] for example, and their usefulness
as intermediates in organic synthesis, they have recently at-
tracted much attention.[3,6,7] To enhance the productivity and
reduce the reaction time, microwave (MW) heating has
During the last few years we have focused[10–13] on devel-
oping PdII-catalyzed oxidative Heck reactions,[14] and we
now aim to extend the useful concept of PdII-catalysis to
other coupling reactions. To the best of our knowledge, the
use of PdII catalysis and arylboronic acids or aryl trifluoro-
borates as starting materials remains totally unexplored in
À
the field of C P bond formation. Furthermore, the stability,
low toxicity, commercial availability, and unique functional-
group tolerance of boronic acids make a PdII method an at-
tractive alternative to the Pd0-catalyzed version. The same
applies to the more recently introduced aryl trifluorobo-
rates, which represent a new valuable class of arylation
agents.[15] In an effort towards the development of smooth
[a] Dr. M. Andaloussi, J. Lindh, J. Sꢀvmarker, Prof. M. Larhed
Department of Medicinal Chemistry
Organic Pharmaceutical Chemistry
Uppsala University, BMC, Box-574
751 23 Uppsala (Sweden)
À
C P bond-forming methods, we decided to explore P-aryl-
ation reactions of H-phosphonate diesters with arylboronic
acids and aryltrifluoroborates under our recently employed
PdII-catalyzed Heck conditions.[13] Thus, we herein report
our contribution towards achieving a general reaction proto-
col to gain easy access to aryl phosphonate compounds. Fur-
thermore, to obtain more information regarding the catalytic
cycle and involved palladium intermediates we decided to
study the live reaction by using online ESIMS.
Fax : (+46)18-471-44-74
E-mail: Mats@orgfarm.uu.se
[b] Dr. P. J. R. Sjçberg
Department of Physical and Analytical Chemistry
Uppsala University, BMC, Box-599, 751 23, Uppsala (Sweden)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901473.
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Results and Discussion
To include aryl trifluoroborates as aryl precursors, a quick
scan of suitable reaction conditions was performed. Employ-
ing the conditions from entry 5 in Table 1 resulted in little
Based on our previous work[12,13] we chose [Pd
ACTHNUTRGNEN(UG OAc)2]/
dmphen (dmphen=2,9-dimethyl-1,10-phenanthroline) as the
product formation. We found, however, that [Pd
ACHTNUGRTNE(NGNU O2CCF3)2]
À
catalytic system to promote the C P bond-formation reac-
was superior to [Pd(OAc)2] as catalyst and that good yields
of aryl phosphonates 2 were obtained after 20 min of radia-
tion at 1208C by using MeOH as the solvent.
ACHTUNGTRENNUNG
tion. The utilization of the air-stable dmphen bidentate
ligand allows for the use of non-inert conditions, which facil-
itates the practical procedures. Furthermore, by using a bi-
dentate ligand the catalytic cycle is expected to proceed
through cationic PdII complexes.[16] We selected the reaction
between p-tolylboronic acid and diethyl phosphite as a suita-
ble model reaction. A number of solvents, reoxidants, and
temperatures were investigated by using sealed vessels and
30 min of controlled single-mode MW heating. The reaction
mixture contained diethyl phosphite (0.5 mmol), p-tolylbor-
The scope of the base-free PdII-catalyzed P arylation was
investigated with respect mainly to the aryl moiety
(Table 2). A good yield of 67% was obtained for the elec-
tron-rich 3,4-dimethoxy-substituted phenylboronic acid 1a
(Table 2, entry 1). Employing the sterically demanding o-tol-
ylboronic acid 1b (Table 2, entry 2) resulted in a reduced
yield (70%) compared with the para-substituted counterpart
1d (Table 1, entry 5; 89%). The same trend could not be ob-
served for the corresponding aryl trifluoroborates 1c and 1e
which produced 2b and 2c in 77 and 81% yield, respectively
(Table 2, entries 3 and 5). The arylation of dimethyl phos-
phite essentially provided the same yield (85%) of 2d as the
corresponding arylation of diethyl phosphite (Table 1,
entry 5 and Table 2, entry 6). Additionally, full conversion of
the coupling of p-tolylboronic acid with diethyl phosphite or
dimethyl phosphite was achieved without p-BQ in an open
vessel at room temperature in 24 h and 48 h, respectively
(Table 2, entries 4 and 6), whereas full conversion of the
same coupling reactions was attained after 30 min of micro-
wave irradiation at 1008C (Table 1, entry 5). Phenylphos-
phite 2e was isolated in a useful yield of 65% by using phe-
nylboronic acid 1 f as the arylating agent (Table 2, entry 7).
Interestingly, the use of phenyl trifluoroborate 1g provided
the same product (2e) in a substantially higher yield of 85%
(Table 2, entry 8). Furthermore, the naphthyl and biphenyl
phosphonate 2 f and 2g could be isolated in excellent yields
(Table 2, entries 9 and 10). The use of electron-poor arylbor-
onic acids 1j and 1l resulted in good isolated yields of the
corresponding phosphonate products 2h and 2j (Table 2, en-
tries 11 and 13), an outcome that is not always realized in
PdII transformations with electron-poor arylboronic acids.[11]
Owing to competing debromination, a significantly lower
yield of product 2i was obtained by using m-bromo aryl tri-
fluoroborate 1k as compared with the p-bromo substituted
arylboronic acid counterpart 1j (Table 2, entries 12 and 11).
Excellent chemoselectivity was observed in the coupling of
both 4-bromophenylboronic acid 1j and 3-bromophenyltri-
fluoroborate 1k, without any trace of the Suzuki product
(Table 2, entries 11 and 12). Aryltrifluoroborate 1m provid-
ed a somewhat lower yield of product 2j as compared with
the corresponding arylboronic acid 1l (67%), indicating that
electron-poor aryltrifluoroborates might be inferior as aryl
precursors for this type of transformation. The ester-substi-
tuted arylboronic acid 1n gave 51% isolated yield of prod-
uct 2k, without any detected traces of ester hydrolysis
(Table 2, entry 15). The only studied vinylboronic acid 1o
resulted in a less satisfying yield of 37% of product 2l
(Table 2, entry 16).
onic acid (1d, 1 mmol), [PdACHTNUGRTENUNG(OAc)2] (4 mol%), dmphen
(6 mol%), reoxidant (0.5 mmol), and solvent (2 mL). The
comparison between five commonly employed solvents
(Table 1, entries 1–5) led to the choice of DMF as a suitable
solvent for this reaction (Table 1, entry 5). p-Benzoqui-
Table 1. Investigation of reaction parameters.[a]
Entry
Solvent
Reoxidant
T [8C]
Isolated yield
of 2c [%]
1
2
3
4
5
6
7
8
MeCN
dioxane
H2O
p-BQ
p-BQ
p-BQ
–
p-BQ
[CuACTHNGURETNNU(G OAc)2]
PhCO3tBu
H2O2
air
p-BQ
p-BQ
p-BQ
100
100
100
100
100
100
100
100
100
80
67
20
0
acetone
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
0
89
13
12
5
9
8
10
11
12
41
39
70[b]
60
100
[a] Reaction conditions: A 5 mL microwave-transparent vial was charged
with ArB(OH)2 (1.0 mmol), diethyl phosphite (0.5 mmol), reoxidant
(0.5 mmol), [PdACHTUNGTRENNUNG(OAc)2] (0.02 mmol), dmphen (0.03 mmol), and solvent
(2 mL). The vial was sealed under air and thereafter exposed to micro-
wave heating for 30 min at the temperature denoted in the table.
[b] Heated with conventional heating instead of MW heating and run
overnight to reach full conversion.
none[17] (p-BQ) was identified as the most efficient of the re-
oxidants examined. All attempts to reduce the reaction tem-
perature below 1008C resulted in lowered yields (Table 1,
entries 10 and 11). Thus, the conditions from entry 5 were
selected for further investigation. Finally, one reaction that
used conventional heating instead of MW heating was per-
formed (Table 1, entry 12). The transformation was found to
require a substantially longer reaction time to reach full
conversion. Thus, heating for 3 h in a 1008C oil bath was not
enough, so the reaction was conducted overnight, providing
a 70% isolated yield of 2c.
The ability to use halogen-substituted arylboronic acids,
in which the halide group is left untouched during the P
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II
À
Microwave-Promoted Pd -Catalyzed C P Bond Formation
FULL PAPER
Table 2. PdII-catalyzed synthesis of aryl and vinylphosphonate diesters.[a]
arylACTHNUTRGENUaGN tion, which is much more difficult to achieve when
using Pd0-catalyzed methods,[18] might give access to new
synthetic strategies and new products. As an implementation
of this possibility, a known inhibitor[19] of Mycobacterium tu-
berculosis glutamine synthetase (MTB-GS) was synthesized
by using 3-bromophenylboronic acid and diethyl phosphite
as starting materials (Scheme 1). Aryl phosphonate 2i was
smoothly prepared in 61% yield by using the reaction con-
ditions for arylboronic acids from Table 2. Subsequent CuI-
catalyzed aromatic substitution utilizing unprotected gly-
cine[19] provided the final MTB-GS inhibitor in 42% isolated
yield.
Entry Boronic compound
Product
Isolated yield
[%]
1
67
2
3
70
2b
77[b]
4
5
1d
1d
2c
2c
57[c]
81[b]
The first mechanistic proposal for the Pd0-mediated P-
arylACHTNUGRTNEUNG
ation reaction was provided by Hirao,[1] and recently
conducted thorough investigations by Stawinski[20,21] and
Stockland[22] have provided further insights into the reaction
mechanism. It has been suggested that the aryl halide under-
goes oxidative addition to Pd0 followed by coordination of
the H-phosphonate diester nucleophile. A base is needed to
deprotonate the H-phosphonate diester before the arylated
phosphonate diester is quickly generated by reductive elimi-
nation. Interestingly, the methods reported in the literature,
which use Pd0 catalysis for the synthesis of aryl and vinyl
phosphonate compounds, highlight the importance of base
in the reaction.[1,6,20,21] In our protocol no base is added,
which raises questions regarding the catalytic cycle. To study
the reaction mechanism we decided to use ESIMS analysis,
a technique which has been successfully employed in study-
ing a number of palladium-catalyzed reactions.[12,23] The
ESIMS analysis was performed to detect cationic palladium-
6
7
8
85, 61[d]
65
2e
85[b]
9
90, 78[c]
10
11
12
13
83
75
À
containing intermediates in ongoing C P bond-forming re-
actions. The investigation was initiated by analysis of the
room-temperature reaction with 1h and diethyl phosphite
depicted in Table 2, entry 9. Aliquots were withdrawn from
the reaction mixture every second hour (during 8 h) and
then diluted ten times with DMF. The initial ESIMS(+)
studies indicated that most relevant monocharged organo-
palladium complexes could be observed after 4 h of reaction
time, which prompted us to run ESIMS analysis after 4 h for
all of the reactions studied. Through the use of tandem mass
spectrometry (MS/MS), more accurate structural proposi-
tions could be made for each of the detected ions. The iso-
topic ions with the strongest and the second strongest inten-
sity for each organopalladium complex (containing 106Pd and
108Pd, respectively) were selected for further MS/MS(+)
analysis. The different complexes were labeled and classified
according to where in the proposed catalytic cycle they may
occur (Scheme 2). To validate further and to characterize
the proposed observed complexes better, a series of addi-
tional reactions were analyzed by ESIMS(+) and MS/
MS(+) (see the Supporting Information). Each component
in the standard reaction with diethyl phosphite and 1h was
substituted for a chemically equivalent one, providing the
analogous Pd complexes in situ but with different m/z ratios.
Hence, 1-naphthylboronic acid (1h) was exchanged for p-
tolylboronic acid (1d), diethyl phosphite for dimethyl phos-
phite, and dmphen for the related bathocuproine (bathocu-
44[c]
67
14
15
2j
57[b]
51
16
37
[a] Reaction conditions:
(1.0 mmol), diethyl phosphite (0.5 mmol), p-benzoquinone (0.5 mmol),
[Pd(OAc)2] (0.02 mmol), dmphen (0.03 mmol), and DMF (2 mL). The
A 5 mL vial was charged with ArB(OH)2
ACHTUNGTRENNUNG
vial was sealed under air and thereafter exposed to MW heating for
30 min at 1008C. Isolated yield>95% pure by GC–MS. [b] A 5 mL vial
was charged with ArBF3K (1.0 mmol), diethyl phosphite (2.0 mmol), p-
benzoquinone (1.0 mmol), [PdACHTUNRTGNEUNG(O2CCF3)2] (0.02 mmol), dmphen
(0.03 mmol), and MeOH (3 mL). The vial was sealed under air and there-
after exposed to microwave heating for 20 min at 1208C. [c] The same re-
action conditions as [a] but performed at room temperature with a reac-
tion time of 24 h and performed in an open vial with air as the reoxidant
(no p-benzoquinone). [d] The same reaction conditions as [c] but with a
reaction time of 48 h.
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M. Larhed et al.
proine=2,9-dimethyl-4,7-di-
phenyl-1,10-phenanthroline).
The different replacements
were evaluated one at a time,
all providing productive cou-
pling reactions to yield 57–78%
of arylated phosphonate 2d and
2 f. The reactions proceeded via
the analogous and chemically
Scheme 1. Synthesis of an inhibitor of Mycobacterium tuberculosis glutamine synthetase (MTB-GS).
equivalent Pd intermediates according to ESIMS and MS/
MS analyses, supporting the assignment of Pd complexes A
and B (see Figure 1 and the Supporting Information for de-
tails).
Although recognizing that neutral intermediates cannot
be observed by ESIMS analysis, that all MS-detected cation-
ic complexes might not be catalytically active, and the possi-
bility that some cations might actually form in the instru-
ment, the findings from the ESIMS investigation support a
catalytic cycle that includes transmetalation of the boronic
acid and nucleophilic coordination of the diethyl phosphite
(Scheme 2). Complexes A1–A3 (Figure 1) are believed to
exist in equilibrium with each other and to serve as starting
PdII complexes. Based on the ESIMS studies, the reaction
differs from the Pd0-catalyzed version in the formation of
the aryl–palladium species (complexes B1–B3, Figure 1),
which are formed through transmetalation instead of oxida-
tive addition. The generation of the reductive elimination
precursor C proceeds, after dissociation of the phosphite
anion and subsequent transmetalation with 1, by coordina-
Scheme 2. Proposed plausible catalytic cycle based on ESIMS-detected
cationic PdII complexes.
Figure 1. ESIMS(+) spectrum for the reaction of 1h and diethyl phosphite at ambient temperature including MS/MS analysis of m/z for 106Pd B3.
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II
À
Microwave-Promoted Pd -Catalyzed C P Bond Formation
FULL PAPER
tion of the neutral phosphite nucleophile as in the Pd0-cata-
lyzed reaction, and subsequent loss of a proton (Figure 1).
Alternatively, and perhaps more likely, complex C is directly
formed in an associated manner, A to C, without dissocia-
tion of the phosphite anion.
Conclusion
This novel PdII-catalyzed method for efficient P arylation of
dialkyl phosphites with arylboronic acids or aryl trifluorobo-
rates might give access to new aryl phosphates, which can be
of potential interest in many fields of organic chemistry. The
reaction rapidly proceeds with high chemoselectivity under
non-inert conditions with MW irradiation and might also be
performed under very mild conditions at room temperature
in an open vessel. Contrary to the Pd0-catalyzed P-arylation
reactions, this C P coupling can be carried out under neu-
tral to acidic conditions, thereby substantially contributing
to the versatility of transition-metal-mediated C P bond for-
mations. The suggested catalytic cycle is supported by online
The neutral cis-complex C (Scheme 2) is undetectable by
MS studies and is probably highly reactive, providing the
arylated phosphonate and Pd0 complex D by reductive elim-
ination.[22] Finally, Pd0 species D is oxidized by p-BQ to re-
generate the PdII complex A.[24] Contrary to all published
Pd0-catalyzed P-arylation reactions, no external base is
added to the reaction mixture, although it has been postulat-
ed as a requirement for a base to deprotonate the H-phos-
phonate diester in order for it to act as nucleophile.[20]
Under our conditions, the measured pH of the reaction mix-
ture was about 6 at the start of the reaction and decreased
to ꢀ3 when full conversion was reached (after 30 min of
MW at 1008C). To examine if the reaction would benefit
from the addition of a base, the reaction between 1i and di-
ethyl phosphite was performed with the addition of Et3N
(2 equivalents, pH of reaction mixture ꢀ9–10), which did
not provide any product 2g. Neither was the expected biaryl
Suzuki-type product formed. To examine the pH-range in
which the reaction was efficient, HOAc (2 equivalents) was
added yielding product 2g in 80% isolated yield (pH of re-
action mixture ꢀ4–5). This outcome was almost identical to
the result without addition of HOAc (83% 2g; Table 2,
entry 10). By employing TFA (2 equivalents, TFA=trifluor-
oacetate), product 2g was obtained in 68% isolated yield
(pH of reaction mixture ꢀ1). The lower yield with TFA can
be explained by extensive protodeboronation of 1i. Based
on these experiments, it can be concluded that deprotona-
tion of the phosphite prior to the PdII binding is not necessa-
ry under these conditions, and that no added base is neces-
sary to deprotonate the metal-coordinated nucleophile. In-
tramolecular deprotonation by dmphen is one possible ex-
planation to how the PdII-bound phosphite is deprotonated.
It is also possible that p-benzoquinone might act as base, al-
though the room temperature reactions were carried out in
the absence of p-BQ and still provided highly productive re-
actions (Table 2, entries 4, 6 and 9). Evaluation of other Pd
À
À
ESIMS(+) and MS/MS(+) analyses.
Experimental Section
For experimental details, see the main text and the Supporting Informa-
tion.
Acknowledgements
We gratefully acknowledge the Swedish Research Council and the Knut
and Alice Wallenberg Foundation. We also thank Dr. Peter Nilsson and
Dr. Luke Odell for critical review of this paper.
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(dba)3] was as efficient as with the PdII
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(Figure 1),
ACHTUNGTRENNUNG
is
the
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complex
[Pd-
(dmphen)(P(O)(OR)2)2].[25]
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Published online: October 23, 2009
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