Phosphorus-carbon bond formation: Palladium-catalyzed cross-coupling of H-phosphinates and other P(O)H-containing compounds

Article abstract of DOI:10.1002/adsc.201300069

Two generally applicable systems have been developed for the cross-coupling of P(O)H compounds with C_sp2-X and related partners. Palladium catalysis using a ligand/additive combination, typically either xantphos/ethylene glycol or 1,1-bis(diphenylphosphino)ferrocene/1,2- dimethoxyethane, with diisopropylethylamine as the base, proved to be generally useful for the synthesis of numerous P-C containing compounds. Routinely, 2 mol% of catalyst are employed (less than half the amount typically employed in most other literature reports). In most cases, excellent results are obtained with a variety of electrophiles (RX, where R=alkenyl, allyl, alkynyl, etc.). The full account of our studies is disclosed, including tandem hydrophosphinylation/ coupling and coupling/coupling for doubly catalytic phosphorus-carbon bond formation. The methodology compares favorably with any existing literature report. The use of an additive appears to be a generally useful strategy to control the reactivity of phosphinylidene compounds. Copyright

Full text of DOI:10.1002/adsc.201300069

FULL PAPERS
DOI: 10.1002/adsc.201300069
Phosphorus-Carbon Bond Formation: Palladium-Catalyzed
Cross-Coupling of H-Phosphinates and Other P(O)H-Containing
Compounds
Olivier Berger,a Christelle Petit,a Eric L. Deal,a and Jean-Luc Montchampa,*
a
Department of Chemistry, Box 298860, Texas Christian University, Fort Worth, Texas 76129, USA
E-mail: j.montchamp@tcu.edu
Received: January 23, 2013; Published online: April 30, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300069.
Abstract: Two generally applicable systems have electrophiles (RX, where R=alkenyl, allyl, alkynyl,
been developed for the cross-coupling of P(O)H etc.). The full account of our studies is disclosed, in-
ꢀ
compounds with Csp2 X and related partners. Palla- cluding tandem hydrophosphinylation/coupling and
dium catalysis using a ligand/additive combination, coupling/coupling for doubly catalytic phosphorus-
typically either xantphos/ethylene glycol or 1,1’-bis- carbon bond formation. The methodology compares
A
favorably with any existing literature report. The use
with diisopropylethylamine as the base, proved to be of an additive appears to be a generally useful strat-
ꢀ
generally useful for the synthesis of numerous P C egy to control the reactivity of phosphinylidene com-
containing compounds. Routinely, 2 mol% of catalyst pounds.
are employed (less than half the amount typically
employed in most other literature reports). In most Keywords: aryl chlorides; cross-coupling; palladium;
cases, excellent results are obtained with a variety of H-phosphinates; phosphinylidenes; tautomerization
Introduction
largely controlled by the tautomeric equilibrium be-
tween the so-called P(V) form [P(O)H] and the PACHTUNGTRENNUNG(III)
Phosphorus-carbon bond formation has become form [P(OH)] [Eq. (1)].[5] An additive (or a catalyst)
a very active research area in modern organophos- should be able to affect this equilibrium and increase
phorus chemistry due to the importance of the com- the concentration of the PACTHUNRTGNEUNG(III) tautomer thereby en-
pounds in a variety of fields, from material science to hancing the scope of various reactions since the avail-
ligands in transition metal-catalyzed reactions, from ability of this species controls most of the phosphiny-
metal-organic frameworks (MOFs) to biologically lidene reactivity.
active molecules.[1] As a result, intense research has
been devoted to this topic in recent years.[2] Over the
past decade, our laboratory has reported various syn-
thetic methodologies for the preparation of H-phos-
phinates and disubstituted phosphinates,[3] and we re-
ꢀ
cently disclosed the first general P C bond formation
using the palladium-catalyzed reaction of H-
phosphin
porting the full account of our studies concerning the
palladium-catalyzed cross-coupling of P(O)H com- between a phosphorus reagent and Csp2 X have ap-
ACHTUNGTRENNUNG
ates with aryl chlorides.[4] Below, we are re-
Numerous reports of metal-catalyzed cross-coupling
ꢀ
pounds with Csp2 and related electrophiles.
peared[6–11] since Hiraoꢀs seminal reports.[12] However,
Phosphinylidene [P(O)H]-containing compounds to date there is still no truly general set of conditions
constitute a significant portion of organophosphorus that are applicable to a broad range of both P(O)H
functionalities, including: phosphinates [ROP(O)H2], nucleophiles and carbon electrophiles. Our own con-
H-phosphinates [R1P(O)(OR)H], H-phosphonates tributions[13] initially focused on the reactions of phos-
[(RO)2P(O)H], and secondary phosphine oxides phinates (pioneered by Schwabacher and Holt),[11a–e]
[R2P(O)H]. The chemistry of these compounds is with the added complication that these reagents are
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Olivier Berger et al.
FULL PAPERS
powerful reducing agents so that competing transfer
hydrogenation[14] needed to be suppressed. More re-
cently, our focus shifted to H-phosphinates.[4,15] Vari-
ous examples of functionalization of R1P(O)(OR)H
through cross-coupling have been reported in the lit-
erature,[11] however, our 2011 communication was the
first to offer a general method in which aryl chlorides
could be employed, using a broadly applicable set of
conditions, lower catalyst loadings, and the use of ad-
ditives like ethylene glycol (EG).[4] Following this
work, we have continued our efforts to develop a syn-
thetic method as generally applicable as possible to
any P(O)H reagent, especially H-phosphinates, but
also H-phosphonates, and secondary phosphine
oxides. We are now reporting the full study of this re-
action.
Our initial cross-coupling of H-phosphinates with
aryl chlorides can be summarized as follows: a Pd/
xantphos (or Pd/dppf) catalyst with a solvent additive
(EG) gave excellent results. Nonetheless, EG some-
times gave significant amounts of transesterified prod-
uct R1P(O)(OCH2CH2OH)Ar, thereby decreasing the
yield of desired product (unless hydrolysis to the cor-
responding phosphinic acid is completed). But the
study proved that EG could be a general solution for
Scheme 1. Mechanistic pathways in the cross-coupling of
phosphinylidene compounds.
the synthesis of phosphinates R1P(O)(OR)Ar, even Reductive elimination then gives the coupling product
with aryl chlorides. Dimethoxyethane (DME) and 7 regenerating the metal catalyst. Strong bases (pKa
propylene glycol (PG) were also identified as other ~18 or above) can deprotonate the P(O)H compound
promising additives.[4]
to form 2 which is an excellent nucleophile. Note that
A possible mechanistic pathway for the cross-cou- the timing of deprotonation 5!6/reductive elimina-
pling of phosphinylidene compounds [phosphinates, tion 6!7 might be reversed (i.e., the phosphonium
H-phosphinates, H-phosphonates, and secondary intermediate could reductively eliminate before de-
phosphine oxides, R1R2P(O)H] is summarized in protonation takes place). Because the reductive elimi-
Scheme 1. With phosphinates [ROP(O)H2, R=M, nation of phosphonium ions is known,[17] this must be
ammonium, H, alkyl], we showed that our metal-cata- operating in some cases, however, it is likely that the
lyzed hydrophosphinylation chemistry [addition of relative rates of deprotonation and reductive elimina-
ROP(O)H2 to alkenes and alkynes using Pd and Ni tion depend on specific cases (and base strength).
catalysts][16] relies on the suppression of the compet- With relatively weak bases, such as tertiary amines,
ing transfer hydrogenation pathway, and that large anion 2 is an unlikely intermediate. In the final analy-
bite angle ligands slow down the b-hydrogen elimina- sis, our rationale for successful cross-coupling of H-
tion leading to competing transfer hydrogenation. phosphinates and related P(O)H compounds was
Transfer hydrogenation with phosphinates ROP(O)H2 therefore based on using an additive to promote the
is a preparative method, akin to the more usual labo- P(V) to PACHTNUTRGNE(NUG III) equilibrium [Eq. (1)] and increase the
ratory-scale reaction using formates.[14] On the other concentration of 1, and/or to stabilize the palladium
hand, H-phosphinates R1P(O)(OR)H are much less catalyst.
reducing
than
phosphinates
[hypophosphites,
(III) tautomeric
ROP(O)H2], however, the P(V) to PAHCNUTGTRENNUNG
equilibrium is typically even less favorable, so what is Results and Discussion
gained on one aspect (less competing reduction) is
lost on the other (lower reactivity). The PACHTNUTGRNEUNG(III) tauto- General Conditions
mer 1 is the nucleophile which can either complex to
palladium (ligand-like) leading to reduction/hydro- An investigation on the role of additives in the cross-
phosphinylation pathways, or in cross-coupling reac- coupling of H-phosphinates followed from the discov-
tions displace PdLnX 4 (formed through insertion into ery of EG as an additive in the hydrophosphinylation
the C X bond of 3) producing phosphonium 5. De- of H-phosphinic acids with alkenes and alkynes.[18] As
ꢀ
protonation of 5 into intermediate 6 only requires a model system, the cross-coupling between equimo-
a weak base, whereas 2 can produce 6 directly from 4. lar amounts of OctP(O)ACTHNUTRGNEU(GN OEt)H and bromobenzene
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Phosphorus-Carbon Bond Formation: Palladium-Catalyzed Cross-Coupling of H-Phosphinates
Table 1. Role of solvent and EG in H-phosphinate cross-
Table 2. Role of ligand and additive in H-phosphinate cross-
coupling in toluene.[a]
coupling.[a]
Entry
Solvent
31P NMR yield [%][b]
without EG with EG
Entry
Cosolvent
additive
Ligand
31P NMR
yield [%][b]
1
2
3
4
5
6
EG
EtOH
t-AmOH
CH3CN
DMF
–
30
30
0
(59)
69 (7)
72 (7)
63 (16)
71 (1)
80 (7)
1
2
3
4
5a
5b
6
7
8
none
EG
EG
EG
EG
dppf
none
PPh3
dppf
7
70
85
80
90
96[c]
65
84
81
83
84
74[d]
72
0
5
7
xantphos
toluene
[a]
Conditions: the reactions were conducted at reflux using
solvent or solvent/EG (9:1 v/v), or at 1158C with neat
EG or DMF.
Determined after addition of EtOH to obtain a homoge-
neous mixture. In a few cases, some 2-hydroxyethyl ester
also formed and the yield is indicated in parentheses.
EG
EG
EG
EG
EG
dppe
dppp
DBFphos
BINAP
PS-nixantphos
[b]
9
10a
10b
11
12a
12b
12c
PG
dppf
none
dppf
xantphos
DME
96
81
was chosen. Table 1 shows the role of the solvent in
the absence or presence of EG. For these initial stud-
ies, (i-Pr)2NEt and dppf were selected as ligand and
base, respectively, based on our earlier work on the
cross-coupling of (i-PrO)2P(O)H. Regardless of the
solvent, addition of EG consistently gives outstanding
increases in yields. Small and variable amounts of
transesterification to the 2-hydroxyethyl ester are also
observed. Using neat EG (entry 1) instead of as an
additive with other solvents does not give a higher
[a]
Conditions: the reactions were conducted at reflux using
toluene/additive (9:1 v/v). 2.2 mol% of bidentate ligands,
or 4.4 mol% for PPh3.
Determined after addition of EtOH to obtain a homoge-
neous mixture.
[b]
[c]
[d]
PdCl2 was used instead of Pd
Obtained after reusing the catalyst from entry 10a.
ACHTUNGERTN(NUNG OAc)2.
yield of cross-coupling product. The effect is seen as the nature of the ligand has a significant but small-
even with other protic solvents (entries 2 and 3), in er effect.
which case the yields are doubled. The effect of EG is
even more dramatic with non-protic solvents (en-
tries 4–6).
Scope of the Reaction
Because toluene gave the best results in the above
study, the role of other parameters was examined At this point, the scope of the reaction was explored.
next with this solvent (Table 2). With EG as the addi- Bromobenzene is a moderately challenging substrate
tive, the yields were consistently high, regardless of in cross-coupling reactions. As we reported in the
the ligand employed, and even successful in the ab- communication, even aryl and heteroaryl chlorides
sence of ligand (entry 2). Nonetheless xantphos gave were successfully coupled to various ethyl alkyl-H-
the best results (entry 5). When the additive was phosphinates [RP(O)ACTHNUTRGNE(NUG OEt)H, R=Oct, Cy, 4-phenyl-
switched from EG to PG the yield decreased a little butyl] in moderate to good isolated yields. Scheme 2
(entry 11 versus entry 4). Using DME (entry 12) also summarizes these results.[4]
gave satisfactory results and prevented transesterifica-
In all cases, the EG/xantphos system was employed
tion, but was completely ineffective in the absence of with toluene as the solvent, and in some cases, the use
ligand (entry 12a), but dppf was excellent (entry 12b), of 1.5 equiv. of ArCl gave improved yields. Regard-
and the product was isolated in 87% yield. With xant- less, this was the first general method to cross-couple
[4]
ꢀ
phos as the ligand, EG remained a better additive phosphorus nucleophiles with Csp2 Cl electrophiles.
(entry 12c versus entry 5). Clearly, significant differen-
Continuing these studies, other electrophiles and
ces can be observed depending on the additive and H-phosphinates combinations were studied. Table 3
ligand combination that is selected. Nonetheless, one summarizes the results. Not surprisingly, the cross-
conclusion is that additives play a critical role in the coupling of ethyl octyl-H-phosphinate takes place as
cross-coupling of OctP(O)ACHTUNTRGNEUNG(OEt)H with PhBr, where- expected with additional electrophiles (entries 1–4).
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Table 3. Scope of the H-phosphinate cross-coupling with var-
ious electrophiles.[a]
Entry
X
Product
Isolated yield [%]
(31P NMR yield)
1
2
3
Cl
Br
Br
78 (85)
93 (96)[b]
61 (83)
Scheme 2. Isolated yields for the cross-coupling of RP(O)-
ACHTUNGTRENNUNG(OEt)H with ArCl/HetCl, using Pd/xantphos (2 mol%), (i-
Pr)2NEt (1.3 equiv.) in refluxing toluene/EG (9:1 v/v).[4]
4
5
6
7
OTf
Cl
89 (91)
85 (89)
80 (82)
76 (79)
More interestingly, cross-couplings also took place
satisfactorily with a broad range of electrophiles, such
as benzylic (entry 5), alkenyl (entries 6 and 7), allylic
(entries 8 and 9), and even alkynyl (entries 10 and 11)
substrates. Gaumont and co-workers recently demon-
strated the cross-coupling of secondary phosphine-
boranes with alkynyl bromides as a useful method for
the preparation of alkynyl-phosphorus compounds.[8a]
Butyl cinnamyl- and methyl-H-phosphinates also re-
acted uneventfully with aryl bromides (entries 12 and
13). The product of entry 13 can be converted into
the corresponding phosphindolin-3-one heterocycle
(LDA, 2 equiv., THF, ꢀ788C to room temperature,
89% yield).[19]
Br
Br
8
9
OAc
87 (94)
78 (90)
OCO2Et
10
11
Br
Br
62 (75)
43 (52)
Even the “Ciba-Geigy reagent” MeC
ACHTUNGRTENN(UNG OEt)2P(O)-
ACHTUNGTRENNUNG(OEt)H could be coupled with chlorobenzene, howev-
er the conditions needed to be adjusted in this case
(entry 14b) as although the standard conditions were
ꢀ
successful in terms of overall P C bond formation,
12
13
Br
84 (89)[c]
83 (85)[d]
elimination to PhP(O)
(OEt)C
G
major product (entry 14a). Replacing (i-Pr)2NEt with
K2CO3 prevented the side reaction. This is an impor-
tant reaction because the acetal is a protected ver-
sion/precursor of the corresponding H-phosphinate
ester. Hall and co-workers nicely demonstrated this
approach through the cross-coupling of aryl bromides
under Hirao-type conditions [ArBr (1 equiv.), Et3N
Br
Cl
14a
14b
(33)[e]
64 (73)[f]
[a]
(2 equiv.), 10 mol% Pd
ACHTUNGTERN(NNUG PPh3)4, 7 examples, 65–
See the Supporting Information for details: electrophile
(1 equiv.), (i-Pr)2NEt (1.3 equiv.), Pd(OAc)2/xantphos
89%].[11z]
AHCTUNGTRENNUNG
(2 mol%), toluene/EG (9:1, v/v), 1158C, 24 h.
Microwave heating.
PdCl2/2 PPh3 (2 mol%).
[b]
[c]
[d]
[e]
[f]
Cross-Coupling of Aryl-H-phosphinate Esters
BuOH was used instead of EG.
Also contains 59% of PhP(O)
ACHUTGTNRNE(NUG OEt)CCAHTUNGTRNEN(UGN OEt)=CH2.
Early on, Schwabacher reported the formation of
Ar2P(O)(OR) through Pd-catalyzed coupling between
K2CO3 (0.65 equiv.) was used instead of (i-Pr)2NEt.
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Phosphorus-Carbon Bond Formation: Palladium-Catalyzed Cross-Coupling of H-Phosphinates
(OBu)H with bromobenzene.[a]
Table 4. Optimization study for the cross-coupling of PhP(O)ACHTUNGTRENNUNG
Entry
Solvent
Base
Additive
Ligand
31P NMR yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
BuOH
DME
DME
toluene
DMF
CH3CN
CH3CN
toluene
N
none
EG
EG
DME
BuOH
xantphos
xantphos
xantphos
xantphos
xantphos
xantphos
xantphos
xantphos
xantphos
xantphos
xantphos
dppf
71
80
92[c]
77
84
86
68
71
64
77
94
92
1,3-diphenylurea
methylcellulose
PEG
diglyme
none
none
none
DME
DME
DME
DME
DME
R
E
pyridine
pyridine
pyridine
dppf
dppf
dppf
dppf
30
45
21
62
dppf
96[d]
[a]
Conditions: the reactions were conducted at reflux using toluene, BuOH, DME or CH3CN, and at 1158C with DMF.
Liquid additives were used as 10% v/v.
Determined after addition of EtOH to obtain a homogeneous mixture.
84% isolated yield.
[b]
[c]
[d]
94% isolated yield.
ArI and ROP(O)H2, but the less reactive bromides Presumably because of the latter side reaction, switch-
and triflates failed.[11a] Thus, the cross-coupling be- ing the base from (i-Pr)2NEt to pyridine resulted in
tween PhP(O)
ACHTUNGTRENNUNG
tigated next in some detail (Table 4).
Even in the absence of any additive (entry 1), the DME (entries 4–9). As expected based on the discus-
yield was acceptable. This should be compared with sion above, only a moderate (+10%) or no improve-
Table 1, entry 6, which shows a very low yield of ment was observed when (i-Pr)2NEt is the base. On
cross-coupling for OctP(O)
ACHTUNGTRENNUNG
additive. And so, with PhP(O)AHCNUTGTRENNUNG
of EG improved the yield only slightly (entry 2). The But as an additive using dppf, the results were disap-
reason is likely related to the intrinsically higher con- pointing (entries 13–16). Finally, using propylene
centration of P
phosphinate, so that cross-coupling is faster (see also titative yield (entry 17, 94% isolated).
Scheme 1) and less sensitive to the role of an additive. Unfortunately, attempted reactions with chloroben-
Indeed, in aryl-H-phosphinates the P(III) tautomer zene gave disappointing results. No matter what the
ACHTUNGTRENNUNG(III) tautomer in the case of phenyl-H- oxide as the HBr scavenger resulted in a nearly quan-
AHCTUNGTRENNUNG
[Eq. (1)] is stabilized by the electron-withdrawing aryl conditions [base: (i-Pr)2NEt, pyridine, tetramethylpi-
moiety (lone pair delocalization) while the phospho- peridine, DABCO, Cy2NMe, N-methylmorpholine,
nium form is simultaneously destabilized.[18] Electron- K3PO4, K2CO3, zinc powder, etc.] or solvent, ligand,
donating substituents (such as alkyl) have the oppo- and additive: the best yield remained below 30%.
site effect: destabilization of the P
bilization of the phosphonium. However, oxidative tive addition into PhCl leads to dominant competing
addition into the P(O)H (potentially leading to trans- side reactions associated with P(III) PhP(OBu)(OH)
ACHTUNGERTN(NUNG III) form and sta- This clearly points to the fact that the slower oxida-
A
ACHTUNGTRENNUNG
fer hydrogenation) is also easier, as well as other com- resulting in poor yields. The most pronounced side-re-
petitive and undesired side-reactions associated with actions were air oxidation to the phosphonate mono-
the P
ACHTUNGTRENNUNG(III) tautomer, such as: air oxidation, transesteri- ester and dealkylation. While freeze-degas-thaw con-
fication, and base-promoted ester dealkylation.[13c] ditions helped slightly with the former, the latter re-
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Olivier Berger et al.
FULL PAPERS
mained a major issue. We therefore reasoned that
changing the ester group to cyclohexyl might solve
this problem. It is standard knowledge that the rate of
SN2 decreases significantly from primary to secondary
alkyls, and by another two orders of magnitude from
isopropyl to cyclohexyl. Also, cyclohexyl H-phosphi-
nates can be prepared easily through Dean–Stark
esterification of the corresponding acid with cyclohex-
anol [Eq. (2)].
The cross-coupling of PhP(O)ACTHNUTRGNE(NUG OCy)H with aryl
chlorides was therefore examined next (Table 5). As
expected, the cyclohexyl ester more resistant to deal-
kylation gave much better results. Isolated yields of
cross-coupling with activated CF3C6H4Cl (entry 4), Scheme 3. Preparation of RP(O)
ACHTUNGRETN(NUNG OCy)H and cross-coupling
using Pd/ligand (2 mol%). All specified yields are for isolat-
ed products. (a) cyclohexanol (2 equiv.), toluene, Dean–
Stark trap, 3 h. (b) BnCl (1 equiv.), PdACTHNURTGNENG(U OAc)2 (2 mol%),
xantphos (2.2 mol%), (i-Pr)2NEt (1.3 equiv.), toluene/EG
(9:1, v/v), reflux, 24 h. (c) chlorobenzene (3 equiv.),
unactivated chlorobenzene (entry 6), and deactivated
2-iodoaniline (entry 7), or 2-bromoaniline (entry 8)
were 95%, 77%, 59%, and 70%, respectively. Even
the sterically hindered 2-iodomesitylene reacts suc-
cessfully (entry 9, 61% isolated yield). This is note-
PdACTHUNTGRENUNG(OAc)2 (2 mol%), xantphos (2.2 mol%), K2CO3
worthy because the cross-coupling of PhP(O)
with iodomesitylene was reported previously
[10 mol% Pd(PPh3)4, propylene oxide, CH3CN] to
proceed in less than 18% yield![11w]
ACHTUNGTRNE(NUNG OMe)H
(0.65 equiv.), DMF/DME (9:1, v/v), 1158C, 48 h. (d) MeI
(1.1 equiv.), DBU (1.1 equiv.), toluene, 08C to room temper-
ature, 16 h. (e) 4-bromopyridine hydrochloride (1 equiv.),
ACHTUNGTRENNUNG
Pd
(OAc)2
(2 mol%),
dppf
(2.2 mol%),
(i-Pr)2NEt
In contrast, our conditions use 5-times less palladi- (2.3 equiv.), DMF/DME (9:1, v/v), 1158C, 24 h. (f) 1-bromo-
naphthalene
(2.2 mol%), propylene oxide (1.3 equiv.), DMF/DME (9:1,
v/v), 1158C, 24 h. (g) 4-CF3C6H4Cl (1.5 equiv.), Pd(OAc)2
(2 mol%), dppf (2.2 mol%), propylene oxide (1.3 equiv.),
DMF/DME (9:1, v/v), 1158C, 24 h.
(1 equiv.),
Pd
(OAc)2
(2 mol%),
dppf
um and result in a better than 3-fold improvement in
yield.
The use of the cyclohexyl ester can also be applied
to other cases (Scheme 3). For example, cross-cou-
pling of cyclohexyl octyl-H-phosphinate 8 with benzyl
ACHTUNGTRENNUNG
Table 5. Cross-coupling of PhP(O)ACHTUNGTRNEUNG
(OCy)H with aryl halides.[a]
Entry
Solvent/additive
Base
Ligand
ArX (equiv.)
Isolated yield [%] (31P NMR yield)[b]
1
2
3
4
5
6
7
8
9
toluene/EG
DMF/EG
pyridine
pyridine
propylene oxide
propylene oxide
propylene oxide
xantphos
xantphos
dppf
dppf
dppf
dppf
dppf
dppf
dppf
CF3C6H4Cl (1.5)
CF3C6H4Cl (1.5)
CF3C6H4Cl (1.5)
CF3C6H4Cl (1.5)
PhCl (1.5)
– (87)
– (90)
– (97)
95 (100)
– (46)
77 (80)
59 (65)
70 (89)
61 (65)[c]
toluene/EG
DMF/DME
DMF/DME
DMF/DME
DMF/DME
DMF/DME
DMF/DME
G
E
G
PhCl (1.5)
2-H2NC6H4I (1.0)
2-H2NC6H4Br (1.0)
MesI (1.5)
[a]
Conditions: the reactions were conducted at reflux using toluene, and at 1158C with DMF. Liquid additives were used as
10% v/v; with base or HX scavenger (1.3 equiv.).
Determined after addition of EtOH to obtain a homogeneous mixture when EG was used.
Contains an additional 23% of transesterification due to iodopropanol.
[b]
[c]
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Phosphorus-Carbon Bond Formation: Palladium-Catalyzed Cross-Coupling of H-Phosphinates
chloride gives the corresponding product 9 in excel-
lent yield (also compare with Table 3, entry 5 for the
ethyl ester). Similarly, a significant yield improvement
is obtained for cross-coupling with chlorobenzene to
form 10.
Scheme 3 shows several other examples. Cross-cou- isolated but instead the solution (typically 0.5M) in
pling of methyl-H-phosphinate 11 with bromopyridine which it is generated, is used directly.[20]
gives 12. Cristau and co-workers reported the cross-
coupling of ethyl benzyloxymethyl-H-phosphinate
with several aryl halides (no chloride) using Hirao 6H-Dibenzo
conditions [10 mol% Pd(PPh3)4, 3 equiv. Et3N, tolu- (DOPO)
ene, reflux] and obtained the corresponding products
[1,2l5]oxaphosphinine 6-Oxide
ACHUTGTNRENNUG[c,e]ACHTUTGNRENNUGN
AHCTUNGTRENNUNG
in 27–70% isolated yield (50% with 1-bromonaphtha- DOPO is an important H-phosphinate used in the
lene).[11u] Using cyclohexyl benzyloxymethyl-H-phos- flame-retardant industry. Beletskaya and co-workers
phinate 13, compounds 14 and 15 are obtained in ex- studied the arylation of DOPO with iodides and bro-
cellent yields. Clearly, the combination of our cross- mides and 5 mol% palladium. The isolated yields
coupling conditions with the more resistant cyclohexyl were in the 75% range with iodides, and 50% with 4-
ester delivers much better results (87% isolated yield NCC6H4Br.[11t] Using our conditions, DOPO reacts
of 14 versus 50% reported by Cristau). Cyclohexyl uneventfully in moderate yields, as shown in Table 6.
phosphinate [CyOP(O)H2] can also be prepared in The reactions were slow so extended times (48 h) re-
excellent yield through the Dean–Stark esterification sulted in improved yields (entry 2a versus 2b). This
of H3PO2 [Eq. (3)]. As usual, the phosphinate is not constitutes the first cross-coupling of DOPO with any
aryl chloride.
Table 6. Cross-coupling of DOPO with aryl halides.[a]
H-Phosphonate Diester Cross-Coupling
As mentioned in the introduction, the metal-catalyzed
cross-coupling of H-phosphonate diesters has been
extensively studied.[2,6,12] We were the first to report
the successful use of aryl chlorides in low to moderate
Entry
Time
[h]
ArX
Yield [%]
yields.[6c] Addition of DME as the additive results in
significant improvements (Table 7).
N
(31P NMR yield)
1
2a
2b
3
48
24
48
48
48
4-NCC6H4Br (1.0)
4-CF3C6H4Cl (1.5)
68 (83)
– (49)
59 (70)
65 (75)
55 (56)[b]
Interestingly, the reaction of 3-amino-2-bromopyri-
dine (entry 6) worked very well, whereas Heinicke
studied a broad range of conditions and obtained only
4-EtO2CC6H4Cl (1.5)
PhCl (3.0)
26% yield with 10 mol% palladium and PACHTUNGTRENNUNG(OEt)3
4
while Hirao-type conditions or stoichiometric nickel
were reported to fail completely.[21]
[a]
Conditions: the reactions were conducted at 1158C.
K2CO3 (0.65 equiv.) was used instead of (i-Pr)2NEt.
[b]
Table 7. Cross-coupling of (i-PrO)2P(O)H with aryl chlorides.[a]
Entry
ArX (phosphite:ArX
equivalent ratio)
Isolated yield [%]
without DME[b]
Isolated yield [%] (31P NMR yield)
with DME
1
2
3
4
5
6
4-NCC6H4Cl (1.2:1.0)
4-CF3C6H4Cl (1.0:1.0)
4-CF3C6H4Cl (1.2:1.0)
57
22
–
61 (64)
52 (68)
61 (70)
63 (78)
– (42)
4-EtO2CC6H4Cl (1.2:1.0)
PhCl (1.2:1.0)
3-amino-2-bromopyridine (1.2:1.0)
44[c]
– (22)
–
87 (100)
[a]
Conditions: the reactions were conducted at 1158C. [b] From ref.[6c] The ratio (i-PrO)2P(O)H:ArCl was 1.2/1.0.
With 4-MeO2CC6H4Cl.
[c]
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Olivier Berger et al.
FULL PAPERS
Table 8. Cross-coupling of Ph2P(O)H with aryl chlorides.
Entry
ArCl (equiv.)
Isolated yield [%]
(31P NMR yield)
1
2
3
4
5
4-NCC6H4Cl (1.5)
4-CF3C6H4Cl (1.5)
4-EtO2CC6H4Cl (1.5)
PhCl (1.5)
96 (97)
93 (94)
96 (100)
– (36)
PhCl (3.0)
78 (81)[a]
[a]
K2CO3 (0.65 equiv.) was used instead of (i-Pr)2NEt.
Diphenylphosphine Oxide Cross-Coupling
To the best of our knowledge, a successful Pd-cata-
lyzed cross-coupling of Ph2P(O)H with ArCl has not
been reported previously. Table 8 summarizes our re-
sults. Activated (electron-poor) chlorides reacted in
excellent yields, but chlorobenzene was unsatisfactory
unless an excess was employed (entry 5).
Scheme 4. Tandem cross-coupling/cross-coupling.
Tandem Reactions
Our laboratory has reported a variety of methods for
the preparation of H-phosphinate esters.[3,13,16] There-
fore, some tandem reaction sequences were investi-
gated next. First, the cross-coupling/cross-coupling re-
action was studied (Scheme 4).
Cross-coupling of CyOP(O)H2 to form symmetri-
cally disubstituted Ar2P(O)ACTHUNTGRNEUNG(OCy) 16 and 17 worked
well using toluene/DME as the solvent (64–83%).
Schwabacher reported the synthesis of (p-
MeC6H4)2P(O)
luene (but bromides failed).[11a] Unsymmetrical diaryl-
ACHTUNGTRENNUNGphosphinate 18 could also be synthesized without any
difficulty. Here, the use of the cyclohexyl ester is im-
portant to minimize side reactions as was discussed
above.
ACHTUNGTRENNUNG(OMe) in 55% yield using 4-iodoto-
Scheme 5. Tandem hydrophosphinylation/cross-coupling.
Second, the tandem palladium-catalyzed hydro- phinate (Scheme 6). Cross-coupling of anilinium hy-
phosphinylation/cross-coupling was briefly investigat- pophosphite as we described previously,[13] produces
ed (Scheme 5). The hydrophosphinylation of 1-octene butyl benzyl-H-phosphinate, which is then coupled
was conducted in toluene (in order to avoid a solvent under our present conditions to form butyl benzyl-
switch) as described previously using EtOP(O)H2 phenylphosphinate 23 in good combined yield. Simi-
(2 equiv.) with Pd/xantphos (2 mol%). Cross-coupling larly, our nickel-catalyzed hydrophosphinylation[16b] of
was conducted directly on the crude reaction mix- 4-octyne can be followed by cross-coupling to form
tures. Ethyl aryl-octylphosphinates 19–22 were ob- ethyl phenyl-(1-propylpent-1-enyl)phosphinate 24 in
tained in moderate to good overall yield (51–82%), 90% isolated yield. Notably, we originally reported
with the same palladium catalyzing both steps.
the preparation of 24 in 58% isolated yield, but using
Other tandem sequences can be employed for dual Hirao-type conditions [2 mol% Cl2PdACTHNUTRGNE(NUG PPh3)2 with
P C bond formation of unsymmetrically substituted Et3N as base] for the cross-coupling step.[16b] Once
phosphinates without intervening purification of both again, this illustrates the very significant improvement
the phosphinate ester and the intermediate H-phos- that additives offer.
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Phosphorus-Carbon Bond Formation: Palladium-Catalyzed Cross-Coupling of H-Phosphinates
Scheme 7. Cross-coupling of phenyl-H-phosphinic acid with
allylic or benzylic alcohols.
ꢀ
ꢀ
Scheme 8. Hydrophosphinylation reactions with Pd/dppf and
DMF/DME.
Scheme 6. Tandem esterfication/P C/P C bond formations
without intermediate purification.
Miscellaneous Applications
sumably because of stabilization of the P
mer through hydrogen bonding, but also drying
ACHTUNGTRENUN(NG III) tauto-
The use of an additive is not limited to the cross-cou- through the use of a Dean–Stark trap or molecular
ꢀ
pling of Csp2 X (and related) electrophiles with phos- sieves was necessary. Therefore, phenyl-H-phosphinic
phinylidene P(O)H nucleophiles. The present studies acid was reacted with cinnamyl alcohol and 1-naph-
were prompted by the discovery that EG allowed the thylmethanol, respectively, using DMF/DME in the
hydrophosphinylation of H-phosphinic acids with al- absence of any drying process (Scheme 7). In the case
kenes [Eq. (4)].[9]
of cinnamyl alcohol, our original conditions gave
a higher yield of product 25 (100%). On the other
hand, with 1-naphthylmethanol, the present condi-
tions give a significantly improved yield of 26 (89%
versus 71%).
Other reactions are shown in Scheme 8. Whereas
a few hydrophosphinylation reactions of terminal al-
kynes have been described with ArP(O)(OR)H,[22]
the addition to internal alkynes, and the use of inex-
However, it was clear that EG played an active role pensive dppf are unprecedented. The preparation of
as the intermediate 2-hydroxyethyl ester. Based on addition products 27 and 28 illustrates the importance
the present work, a few reactions were investigated of the additive (DME) in the tautomerization of the
using DME to see if promotion of the tautomeriza- starting H-phosphinates.
tion to the P
G
The broad scope of the present cross-coupling also
palladium catalyst was in fact a generally applicable has implications in the synthesis of P-heterocycles.
strategy. Previously, we reported the direct cross-cou- Kuninobu, Yoshida, and Takai, reported recently the
pling of hypophosphorous acid and H-phosphinic formation of dibenzophosphole oxides through the
acids with allylic and benzylic alcohols.[15] For the Pd-catalyzed cyclization of substituted 1-biphenyl-
ꢀ
second P C bond formation from the H-phosphinic phosphine oxides (the precursors were synthesized
acid, t-AmOH was found to be superior to DMF, pre- using Grignard reagents and Cl2PR).[23] In order to ex-
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Olivier Berger et al.
FULL PAPERS
the cyclizations were conducted at the same concen-
tration as in the intermolecular cases (0.2M) with
good results. In both cases 31 and 32 the respective
diastereoisomers (a and b) could be separated readily
by simple chromatography on silica gel. The 6-mem-
bered heterocycle 32 appears to be a novel type of
P,N-heterocyclic ring system.
The role of the additive can be two-fold: (i) stabili-
zation of the palladium catalyst over time (slow-down
of decomposition pathways to metallic palladium),
and (ii) promotion of the P(V) to PACTHNUTRGNE(NUG III) tautomeric
equilibrium [Eq. (1)]. At the very least, the latter
must be operative, and although it is a largely neglect-
ed phenomenon in the literature concerning phosphi-
nylidenes P(O)H, we believe that the control of the
tautomeric equilibrium is a major option to improve
upon known reactions or to develop new reactivity as
shown in Scheme 8. Other designed tautomerization
catalysts could be even more powerful even in re-
duced quantities, and this will be a major focus of our
laboratoryꢀs future studies.
Scheme 9. Cross-coupling of 1-bromobiphenyl with Pd/dppf
and DMF/DME followed by Pd-catalyzed oxidative cycliza-
tion.
Conclusions
Generally useful sets of conditions are described for
the palladium-catalyzed cross-coupling of phosphinyli-
dene compounds P(O)H with various electrophiles,
including activated and unactivated aryl chlorides.
While aryl chlorides have previously been used on
very rare occasions, the present work provides
a broadly successful cross-coupling methodology. Ad-
ditionally, even other electrophiles have not always
led to very high yields before, and several examples
where our conditions offer significant improvements
over literature procedures are provided. In particular,
ethylene glycol (EG) is a successful solvent additive,
especially with xantphos as ligand, or with 1,2-dime-
thoxyethane (DME) in combination with dppf. The
latter is probably the ideal option since transesterifi-
cation is totally avoided, and dppf is one of the cheap-
est and broadly available ligands. Both bisphosphine
ligands (xantphos and dppf) are readily available and
inexpensive, and even other ligands like the ubiqui-
tous triphenylphosphine look promising. For cross-
Scheme 10. Synthesis of P,N-heterocycles via tandem Ka-
bachnick–Fields/Pd-catalyzed cross-coupling.
amine if H-phosphinate 29 can also undergo the anal- coupling reactions, the base was generally (i-Pr)2NEt,
ogous cyclization, the sequence shown in Scheme 9 or in a few cases propylene oxide or potassium car-
was accomplished. Whereas the yield of the corre- bonate, and employing strong bases, such as t-BuOK,
sponding heterocycle 30 was moderate, this kind of is completely avoided. All reactions were conducted
process can now be investigated in more details.
with 2 mol% palladium, which is also an improvement
Finally, in keeping with our ongoing interest in P,N- over other literature methods. Various examples were
heterocycles,[24] P(O)H cross-coupling was briefly in- provided where the use of the additive offers very sig-
vestigated as the key ring-closing step as shown in nificant improvements over other procedures. The use
Scheme 10.
of an additive in the reactions of H-phosphinates, H-
The substrates were synthesized through the Ka- phosphonates, and diphenylphosphine oxide promises
bachnick–Fields reaction (phospha-Mannich),[25] then to extend the range of organophosphorus synthesis.
subjected to our cross-coupling conditions. Notably, The use of cyclohexyl H-phosphinate esters is also de-
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Phosphorus-Carbon Bond Formation: Palladium-Catalyzed Cross-Coupling of H-Phosphinates
After 24 h at reflux, the electrophile (2 mmol, 2 equiv.),
scribed as a general and convenient solution to vari-
ous problems associated with the chemistry of alkyl
H-phosphinate esters (such as competing dealkyla-
tion).
DIPEA (0.23 mL, 1.3 mmol, 1.3 equiv.), toluene (0.5 mL)
and ethylene glycol (0.5 mL) were added. After 24 h at
reflux, the mixture was allowed to cool down to room ten-
perature and the solvent was then removed under vacuum.
The residue obtained was dissolved in EtOAc and washed
with NaHCO3 and brine. The organic layer was dried over
MgSO4, filtered and concentrated under vacuum. The crude
obtained was purified by column chromatography.
The generality of our reaction, along with its use in
tandem processes, provides a significant leap over the
ꢀ
current “state-of-the-art” methodologies in P C
cross-coupling reactions. Overall, the present work is
the first truly general method for the synthesis of vari-
ous organophosphorus compounds via Pd-catalyzed
ꢀ
P C bond formation.
Future studies from our laboratory will focus on
Acknowledgements
the design of P(V) to PACTHUNGTRENNG(U III) phosphinylidene tautome-
This material is based upon work supported by the National
Science Foundation under Grant No. 0953368.
rization catalysts, since this will likely lead to general
improvements not just for metal-catalyzed reactions,
but for organophosphorus synthesis in general, since
the PACHTUNGTRENNUNG(III) tautomer is the key reactive species in the
vast majority of cases.
References
[1] a) R. Engel, Handbook of Organophosphorus Chemis-
try, Marcel Dekker, New York, 1992; b) The Chemistry
of Organophosphorus Compounds, (Ed.: F. R. Hartley),
Wiley, New York, 1996, Volume 4; c) D. E. C. Cor-
bridge, Phosphorus: An Outline of Its Chemistry, Bio-
chemistry and Uses, 5th edn., Elsevier, Amsterdam,
1995; d) Aminophosphonic and Aminophosphinic
Acids: Chemistry and Biological Activity, (Eds.: V. P.
Kukhar, H. R. Hudson), Wiley, Chichester, 2000; e) A.
Kalir, H. H. Kalir, Biological Activity of Phosphonic
and Phosphinic Acids, in: Pataiꢀs Chemistry of Func-
tional Groups: Organophosphorus Compounds, (Ed.:
Z. Rappoport), John Wiley & Sons, Ltd., 1996, p 767;
f) L. D. Quin, A Guide to Organophosphorus Chemis-
try, Wiley, New York, 2000; g) D. S. Flett, J. Organomet.
Chem. 2005, 690, 2426; h) P. Savignac, B. Iorga,
Modern Phosphonate Chemistry, CRC Press, Boca
Raton, 2003; i) K. J. Gagnon, H. P. Perry, A. Clearfield,
Chem. Rev. 2012, 112, 1034; j) C. S. Demmer, N. Krogs-
gaard-Larsen, L. Bunch, Chem. Rev. 2011, 111, 7981;
k) C. Queffꢂlec, M. Petit, P. Janvier, D. A. Knight, B.
Bujoli, Chem. Rev. 2012, 112, 3777.
Experimental Section
Representative Procedure for Cross-Coupling
Procedure A: To a tube was added H-phosphinate (1 mmol,
1 equiv.), PdACHTUNGTRENNUNG(OAc)2 (4.5 mg, 0.02 mmol, 2.0 mol%), xant-
phos (12.7 mg, 0.022 mmol, 2.2 mol%), toluene and ethylene
glycol (4.5 mL:0.5 mL), DIPEA (0.23 mL, 1.3 mmol,
1.3 equiv.) and the electrophile (1 mmol, 1 equiv.). The het-
erogeneous mixture was stirred under a flow of N2 for
10 min and then heated at 1158C for 24 h. After cooling to
room temperature, the mixture was diluted with ca. 2.5 mL
EtOH until homogeneous for 31P NMR spectroscopy of the
crude material. The solvent was then removed under
vacuum and the resulting residue was dissolved in EtOAc
and washed with NaHCO3 and brine. The organic layer was
dried over MgSO4, filtered and concentrated under vacuum.
The crude obtained was purified by column chromatography
using mixtures of hexanes and EtOAc.
Procedure B: To
(1 mmol, 1 equiv.),
a
tube was added H-phosphinate
Pd(OAc)2 (4.5 mg, 0.02 mmol,
AHCTUNGTRENNUNG
ꢀ
[2] Reviews on P C bond-formation: a) Q. Xu, L. B. Han,
2.0 mol%), dppf (12.2 mg, 0.022 mmol, 2.2 mol%), DMF and
1,2-dimethoxyethane (4.5 mL:0.5 mL), DIPEA (0.23 mL,
1.3 mmol, 1.3 equiv.) and the electrophile (1 mmol, 1 equiv.).
The mixture was stirred under a flow of N2 for 10 min and
then heated at 1158C for 24 h before cooling to room tem-
perature. The solvent was then removed under vacuum and
the resulting residue was dissolved in EtOAc and washed
with NaHCO3 and brine. The organic layer was dried over
MgSO4, filtered and concentrated under vacuum. The crude
obtained was purified by column chromatography using mix-
tures of hexanes and EtOAc.
J. Organomet. Chem. 2011, 696, 130; b) F. M. J. Tappe,
V. T. Trepohl, M. Oestreich, Synthesis 2010, 3037;
c) D. S. Glueck, Top. Organomet. Chem. 2010, 31, 65;
d) V. P. Ananikov, L. L. Khemchyan, I. P. Beletskaya,
Z. A. Starikova, Adv. Synth. Catal. 2010, 352, 2979;
e) A. L. Schwan, Chem. Soc. Rev. 2004, 33, 218; f) C.
Baillie, J. Xiao, Curr. Org. Chem. 2003, 7, 477; g) R.
Engel, J. I. Cohen, Synthesis of Carbon-Phosphorus
Bonds, 2nd edn., CRC Press, Boca Raton, FL, 2003;
h) I. P. Beletskaya, M. A. Kazankova, Russ. J. Org.
Chem. 2002, 38, 1391; i) M. Tanaka, Top. Curr. Chem.
2004, 232, 25; j) F. Alonso, I. P. Beletskaya, M. Yus,
Chem. Rev. 2004, 104, 3079; k) C. Petit, J.-L. Mon-
Representative Procedure for Tandem
Hydrophosphinylation/Cross-Coupling
ꢀ
tchamp, C P Bond Formation, Vol. 2, Carbon-Heteroa-
tom Cross-Coupling and C C Cross-Couplings of
ꢀ
ꢀ
To
a
solution of ethyl phosphinate (4.0 mL, 2 mmol,
Acidic C H Nucleophiles, in: Science of Synthesis, 3-
2 equiv., 0.5M in toluene) under N2 were added 1-octene
(0.16 mL, 1 mmol, 1 equiv.), PdCl2 (3.55 mg, 0.02 mmol,
2 mol%) and xantphos (12.7 mg, 0.022 mmol, 2.2 mol%).
Vol. set (Eds.: M. Larhed, G. A. Molander, J. P. Wolfe),
Thieme, Stuttgart, 2012; l) Catalytic Heterofunctionali-
zation, (Eds: A. Togni, H. Grꢃtzmacher), Wiley-VCH,
Adv. Synth. Catal. 2013, 355, 1361 – 1373
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1371

Olivier Berger et al.
FULL PAPERS
Weinheim, 2001; m) Metal-Catalyzed Cross-Coupling
Reactions, (Eds.: F. Diederich, P. J. Stang), Wiley-VCH,
Weinheim, 1998.
Cacchi, G. Fabrizi, A. Goggiamani, P. Stabile, Org.
Biomol. Chem. 2010, 8, 4518; c) M. S. S. Adam, M. K.
Kindermann, M. Kçckerling, J. W. Heinicke, Eur. J.
Org. Chem. 2009, 4655; d) J. Fischer, M. Schꢃrmann,
M. Mehring, U. Zachwieja, K. Jurkschat, Organometal-
lics 2006, 25, 2886; e) D. N. Kazul’kin, A. N. Ryabov,
V. V. Izmer, A. V. Churakov, I. P. Beletskaya, C. J.
Burns, A. Z. Voskoboynikov, Organometallics 2005, 24,
3024; f) G. W. Kabalka, S. K. Guchhait, Org. Lett. 2003,
5, 729; g) J. W. Heinicke, N. Gupta, A. Surana, N. Peu-
lecke, B. Witt, K. Steinhauser, R. K. Bansal, P. G.
Jones, Tetrahedron 2001, 57, 9963; h) M. Lera, C. J.
Hayes, Org. Lett. 2000, 2, 3873; i) T. Ogawa, N. Usuki,
N. Ono, J. Chem. Soc. Perkin Trans. 1 1998, 2953; j) L.
Maier, D. Duerr, H. Rempfler, Phosphorus Sulfur
1987, 32, 19.
[3] Reviews: a) J.-L. Montchamp, Phosphorus, Sulfur, Sili-
con
Rel.
Elem.
2012,
DOI:10.1080/
10426507.2012.727925; b) L. Coudray, J.-L. Montchamp,
Eur. J. Org. Chem. 2008, 3601; c) J.-L. Montchamp,
Specialty Chemicals Magazine 2006, 26, 44; d) J.-L.
Montchamp, J. Organomet. Chem. 2005, 690, 2388.
[4] E. L. Deal, C. Petit, J.-L. Montchamp, Org. Lett. 2011,
13, 3270.
[5] a) E. E. Nifant’ev, Russ. Chem. Rev. 1978, 47, 835;
b) V. I. Yudelevich, L. B. Sokolov, B. I. Ionin, Russ.
Chem. Rev. 1980, 49, 46; c) J. Stawinski, A. Kraszewski,
Acc. Chem. Res. 2002, 35, 952.
[6] For H-phosphonate cross-coupling, see: a) K. Xu, H.
Hu, F. Yang, Y. Wu, Eur. J. Org. Chem. 2013, 319;
b) A. Bessmertnykh, C. M. Douaihy, R. Guilard, Chem.
Lett. 2009, 38, 738; c) Y. Belabassi, S. Alzghari, J.-L.
Montchamp, J. Organomet. Chem. 2008, 693, 3171;
d) M. Kalek, A. Ziadi, J. Stawinski, Org. Lett. 2008, 10,
4637; e) B. Whittaker, M. d L. Ruiz, C. J. Hayes, Tetra-
hedron Lett. 2008, 49, 6984; f) C. Huang, X. Tang, H.
Fu, Y. Jiang, Y. Zhao, J. Org. Chem. 2006, 71, 5020;
g) H. Rao, Y. Jin, H. Fu, Y. Jiang, Y. Zhao, Chem. Eur.
J. 2006, 12, 3636; h) D. Gelman, L. Jiang, S. L. Buch-
wald, Org. Lett. 2003, 5, 2315.
[7] Secondary phosphine oxide cross-coupling, see: a) M.
Stankevic, A. Wlodarczyk, Tetrahedron 2013, 69, 73;
b) A. J. Bloomfield, S. B. Herzon, Org. Lett. 2012, 14,
4370; c) X. Zhang, H. Liu, X. Hu, G. Tang, J. Zhu, Y.
Zhao, Org. Lett. 2011, 13, 3478; d) Q.-Y. Zhao, Z.-L.
Yuan, M. Shi, Tetrahedron: Asymmetry 2010, 21, 943;
e) N. T. MsDougal, J. Streuff, H. Mukherjee, S. C.
Virgil, B. M. Stoltz, Tetrahedron Lett. 2010, 51, 5550;
f) B. M. Trost, R. Radinov, J. Am. Chem. Soc. 1997,
119, 5962; g) L. Kurz, G. Lee, D. Morgans, M. J. Wal-
dyke, T. Ward, Tetrahedron Lett. 1990, 31, 6321; h) Y.
Xu, J. Xia, H. Guo, Synthesis 1986, 691; i) Y. Xu, Z. Li,
J. Xia, H. Guo, Y. Huang, Synthesis 1984, 781.
[8] Phosphine-borane cross-coupling, see: a) E. Bernoud,
C. Alayrac, O. Delacroix, A.-C. Gaumont, Chem.
Commun. 2011, 47, 3239; b) J. Li, M. Lutz, A. L. Spek,
G. P. M. Van Klink, G. Van Koten, R. J. M. K. Gebbink,
J. Organomet. Chem. 2010, 695, 2618; c) D. Julienne, O.
Delacroix, A.-C. Gaumont, Phosphorus Sulfur, Silicon
2009, 184, 846; d) D. Julienne, J.-F. Lohier, O. Dela-
croix, A.-C. Gaumont, J. Org. Chem. 2007, 72, 2247;
e) H. Vallette, S. Pican, C. Boudou, J. Levillain, J.-C.
Plaquevent, A.-C. Gaumont, Tetrahedron Lett. 2006,
47, 5191; f) D. Gelman, L. Jiang, S. L. Buchwald, Org.
Lett. 2003, 5, 2315; g) B. H. Lipshutz, D. J. Buzard, C. S.
Yun, Tetrahedron Lett. 1999, 40, 201; h) M. Al-Masum,
T. Livinghouse, Tetrahedron Lett. 1999, 40, 7731.
[9] Secondary phosphine cross-coupling see: a) W. J. Flem-
ing, H. Mꢃller-Bunz, P. J. Guiry, Eur. J. Org. Chem.
2010, 5996; b) M. Murata, S. L. Buchwald, Tetrahedron
2004, 60, 7397; c) O. Herd, A. Hessler, M. Hingst, M.
Tepper, O. Stelzer, J. Organomet. Chem. 1996, 522, 69.
[10] Phosphite and phosphonite cross-coupling, see: a) B. R.
Aluri, B. Niaz, M. K. Kindermann, P. G. Jones, J. W.
Heinicke, Dalton Trans. 2011, 40, 211; b) R. Berrino, S.
[11] Phosphinate and H-phosphinate cross-coupling, see:
a) H. Lei, M. S. Stoakes, A. W. Schwabacher, Synthesis
1992, 1255; b) A. W. Schwabacher, S. Zhang, W. Davy,
J. Am. Chem. Soc. 1993, 115, 6995; c) H. Lei, M. S.
Stoakes, K. P. B. Herath, J. Lee, A. W. Schwabacher, J.
Org. Chem. 1994, 59, 4206; d) A. W. Schwabacher,
A. D. Stefanescu, Tetrahedron Lett. 1996, 37, 425;
e) D. A. Holt, J. M. Erb, Tetrahedron Lett. 1989, 30,
5393; f) Y. Xu, J. Zhang, Synthesis 1984, 778; g) Y. Xu,
Z. Li, J. Xia, H. Guo, Y. Huang, Synthesis 1983, 377;
h) Y. Xu, Z. Li, Synthesis 1986, 240; i) Y. Xu, J. Zhang,
J. Chem. Soc. Chem. Commun. 1986, 1606; j) Y. Xu, H.
Wej, J. Zhang, G. Huang, Tetrahedron Lett. 1989, 30,
949; k) T. Yamagishi, N. Toshiro, T. Yokomatsu, J. Org.
Chem. 2011, 76, 5476; l) J.-N. Volle, D. Filippini, B.
Krawczy, N. Kaloyanov, A. Van der Lee, T. Maurice, J.-
L. Pirat, D. Virieux, Org. Biomol. Chem. 2010, 8, 1438;
m) M. Kalek, J. Stawinski, Tetrahedron 2009, 65, 10406;
n) R. J. Kumar, M. Chebib, D. E. Hibbs, H.-L. Kim,
G. A. R. Johnston, N. K. Salam, J. R. Hanrahan, J. Med.
Chem. 2008, 51, 3825; o) I. P. Beletskaya, N. B. Karl-
stedt, E. E. Nifant’ev, D. V. Khodarev, T. S. Kukhareva,
A. V. Nikolaev, A. J. Ross, Russ. J. Org. Chem. 2006,
42, 1780; p) W. Jiang, G. Allan, J. J. Fiordeliso, O.
Linton, P. Tannenbaum, J. Xu, P. Zhu, J. Gunnet, K.
Demarest, S. Lundeen, Z. Sui, Bioorg. Med. Chem.
2006, 14, 6726; q) C. Huang, X. Tang, H. Fu, Y. Jiang,
Y. Zhao, J. Org. Chem. 2006, 71, 5020; r) J.-L. Pirat, J.
Monbrun, D. Virieux, H.-J. Cristau, Tetrahedron 2005,
61, 7029; s) K. Haaf, Comb. Chem. High Throughput
Screening 2005, 8, 637; t) I. P. Beletskaya, E. G. Nega-
mova, Y. A. Veits, Russ. J. Org. Chem. 2004, 40, 1782;
u) H.-J. Cristau, A. Hervꢂ, F. Loiseau, D. Virieux, Syn-
thesis 2003, 2216; v) G. P. Luke, W. C. Shakespeare,
Synth. Commun. 2002, 32, 2951; w) M. Schuman, Z.
Lopez, M. Karplus, V. Gouverneur, Tetrahedron 2001,
57, 10299; x) C. S. Edlin, D. Parker, Tetrahedron Lett.
1998, 39, 2797; y) Y. Murata, R. M. Woodward, R.
Miledi, L. E. Overman, Bioorg. Med. Chem. Lett. 1996,
6, 2073; z) S. N. L. Bennett, R. G. Hall, J. Chem. Soc.
Perkin Trans. 1 1995, 1145.
[12] a) T. Hirao, T. Masunaga, Y. Ohshiro, T. Agawa, Tetra-
hedron Lett. 1980, 21, 3595; b) T. Hirao, T. Masunaga,
Y. Ohshiro, T. Agawa, Synthesis 1981, 56; c) T. Hirao,
T. Masunaga, N. Yamada, Bull. Chem. Soc. Jpn. 1982,
55, 909.
1372
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1361 – 1373

Phosphorus-Carbon Bond Formation: Palladium-Catalyzed Cross-Coupling of H-Phosphinates
[13] a) J.-L. Montchamp, Y. R. Dumond, J. Am. Chem. Soc.
2001, 123, 510; b) Y. R. Dumond, J.-L. Montchamp, J.
Organomet. Chem. 2002, 653, 252; c) K. Bravo-Altamir-
ano, Z. Huang, J.-L. Montchamp, Tetrahedron 2005, 61,
6315; d) K. Bravo-Altamirano, J.-L. Montchamp, Tetra-
hedron Lett. 2007, 48, 5755; e) K. Bravo-Altamirano, I.
Abrunhosa-Thomas, J.-L. Montchamp, J. Org. Chem.
2008, 73, 2292.
[14] a) G. Brieger, T. J. Nestrick, Chem. Rev. 1974, 74, 567;
b) R. A. W. Johnstone, A. H. Wilby, A. I. Entwistle,
Chem. Rev. 1985, 85, 129; c) R. A. W. Johnstone, A. H.
Wilby, Tetrahedron 1981, 37, 3667; d) R. Sala, G. Doria,
C. Passarotti, Tetrahedron Lett. 1984, 25, 4565; e) S. K.
Boyer, J. Bach, J. McKenna, E. Jagdmann Jr, J. Org.
Chem. 1985, 50, 3408; f) B. T. Khai, A. Arcelli, J. Org.
Chem. 1989, 54, 949; g) A. F. Brigas, R. A. W. John-
stone, Tetrahedron 1992, 48, 7735; h) C. A. Marques,
M. Selva, P. Tundo, J. Chem. Soc. Perkin Trans. 1 1993,
529; i) V. V. Grushin, Chem. Rev. 1996, 96, 2011.
[15] a) L. Coudray, K. Bravo-Altamirano, J.-L. Montchamp,
Org. Lett. 2008, 10, 1123; b) L. Coudray, J.-L. Mon-
tchamp, Eur. J. Org. Chem. 2008, 4101.
[16] a) Y. Belabassi, K. Bravo-Altamirano, J.-L. Mon-
tchamp, J. Organomet. Chem. 2011, 696, 106; b) P. Ri-
biꢄre, K. Bravo-Altamirano, M. I. Antczak, J. D. Haw-
kins, J.-L. Montchamp, J. Org. Chem. 2005, 70, 4064;
c) S. Deprꢄle, J.-L. Montchamp, Org. Lett. 2004, 6,
3805; d) S. Deprꢄle, J.-L. Montchamp, J. Am. Chem.
Soc. 2002, 124, 9386.
[17] For examples, see: a) D. Marcoux, A. B. Charette, Adv.
Synth. Catal. 2008, 350, 2967; b) U. V. Monkowius, S.
Nogai, H. Schmidbaur, Dalton Trans. 2004, 1610;
c) F. Y. Kwong, C. W. Lai, M. Yu, Y. Tian, K. S. Chan,
Tetrahedron 2003, 59, 10295; d) S. E. Martin, M. Bona-
terra, R. A. Rossi, J. Organomet. Chem. 2002, 664, 223;
e) F. Y. Kwong, K. S. Chang, Organometallics 2000, 19,
2058.
[18] C. Petit, F. Fꢂcourt, J.-L. Montchamp, Adv. Synth.
Catal. 2011, 353, 1883.
[19] L. Gavara, C. Petit, J.-L. Montchamp, Tetrahedron Lett.
2012, 53, 5000.
[20] S. Deprꢄle, J.-L. Montchamp, J. Organomet. Chem.
2002, 643–644, 154.
[21] M. S. S. Adam, O. Kꢃhl, M. K. Kindermann, J. W. Hei-
nicke, P. G. Jones, Tetrahedron 2008, 64, 7960.
[22] a) L.-B. Han, C. Q. Zhao, S.-Y. Onozawa, M. Goto, M.
Tanaka, J. Am. Chem. Soc. 2002, 124, 3842; b) L.-B.
Han, C. Zhang, H. Yazawa, S. Shimada, J. Am. Chem.
Soc. 2004, 126, 5080; c) M. Niu, H. Fu, Y. Jiang, Y.
Zhao, Chem. Commun. 2007, 272; d) S. K. Nune, M.
Tanaka, Chem. Commun. 2007, 2858.
[23] Y. Kuninobu, T. Yoshida, K. Takai, J. Org. Chem. 2011,
76, 7370.
[24] a) C. Queffꢂlec, J.-L. Montchamp, Org. Biomol. Chem.
2010, 8, 267; b) C. Queffꢂlec, P. Ribiꢄre, J.-L. Mon-
tchamp, J. Org. Chem. 2008, 73, 8987.
[25] a) X. Cheng, R. Goddard, G. Buth, B. List, Angew.
Chem. 2008, 120, 5157; Angew. Chem. Int. Ed. 2008, 47,
5079; b) E. D. Matveeva, N. S. Zefirov, Dokl. Chem.
2008, 420, 137; c) V. V. Belakhov, Y. D. Shenin, B. I.
Ionin, Russ. J. Gen. Chem. 2008, 78, 305; d) N. S. Zefir-
ov, E. D. Matveeva, ARKIVOC 2008, 1; e) S. Bhagat,
A. K. Chakraborti, J. Org. Chem. 2007, 72, 1263;
f) E. D. Matveeva, T. A. Podrugina, M. V. Prisyajnoy,
N. S. Zefirov, Russ. Chem. Bull. 2006, 55, 1209; g) H.-J.
Cristau, A. Herve, D. Virieux, Tetrahedron 2004, 60,
877; h) E. D. Matveeva, T. A. Podrugina, E. V. Tishkov-
skaya, L. G. Tomilova, N. S. Zefirov, Synlett 2003, 2321;
i) H.-J. Cristau, A. Coulombeau, A. Genevois-Borella,
F. Sanchez, J.-L. Pirat, J. Organomet. Chem. 2002, 643–
644, 381; j) R. A. Cherkasov, V. I. Galkin, Russ. Chem.
Rev. 1998, 67, 857.
Adv. Synth. Catal. 2013, 355, 1361 – 1373
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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