Copper-Catalyzed C?P Cross-Coupling of (Cyclo)alkenyl/Aryl Bromides and Secondary Phosphine Oxides with in situ Halogen Exchange

Article abstract of DOI:10.1002/ejoc.202100456

An efficient protocol for concurrent tandem halogen exchange/C?P cross-coupling of cycloalkenyl bromides and secondary phosphine oxides has been developed. The catalytic system is based on cheap and air-stable copper(I) iodide as the precatalyst, commercially available N,N’-dimethylethylenediamine as the ligand, and Cs₂CO₃ or K₂CO₃ as the base. The use of sodium iodide as an additive reduces the excessive use of organic bromides to near-stoichiometric by promoting the in situ transformation to the corresponding iodides. Diarylphosphine oxides undergo cycloalkenylation with 35–99 % yields and dicyclohexylphosphine oxide with 30–53 % yields. In the case of acyclic alkenyl bromides the cross-coupling products undergo conjugate addition of diphenylphosphine oxide and satisfying yields are observed only for internal olefins. In the case of aryl bromides satisfying yields (43–72 %) are observed only for sterically unhindered arenes or arenes possessing an ortho-directing group. Cycloalkenylphosphine oxides prepared in the cross-coupling reaction undergo base-catalyzed and base-promoted conjugate addition to give bis(phosphinoyl)cycloalkanes.

Full text of DOI:10.1002/ejoc.202100456

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Copper-Catalyzed C-P Cross-Coupling of (Cyclo)alkenyl/Aryl
Bromides and Secondary Phosphine Oxides with in situ Halogen
Exchange
Authors: Paweł Woźnicki and Marek Stankevič
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100456
Link to VoR: https://doi.org/10.1002/ejoc.202100456
01/2020

10.1002/ejoc.202100456
European Journal of Organic Chemistry
FULL PAPER
Copper-Catalyzed C-P Cross-Coupling of (Cyclo)alkenyl/Aryl
Bromides and Secondary Phosphine Oxides with in situ Halogen
Exchange
Paweł Woźnicki*[a] and Marek Stankevič*[b]
[a]
P. Woźnicki
Department of Organic Chemistry, Faculty of Chemistry
Maria Curie-Skłodowska University
Gliniana st. 33, 20-614 Lublin, Poland
E-mail: pawelwoznicki@poczta.umcs.lublin.pl
Dr. M. Stankevič
[b]
Department of Organic Chemistry, Faculty of Chemistry
Maria Curie-Skłodowska University
Gliniana st. 33, 20-614 Lublin, Poland
E-mail: marek.stankevic@poczta.umcs.lublin.pl
Supporting information for this article is given via a link at the end of the document.
Abstract: An efficient protocol for concurrent tandem halogen
exchange/C-P cross-coupling of cycloalkenyl bromides and
secondary phosphine oxides has been developed. The catalytic
system is based on cheap and air-stable copper(I) iodide as the
precatalyst, commercially available N,N’-dimethylethylenediamine as
the ligand, and Cs2CO3 or K2CO3 as the base. The use of sodium
iodide as an additive reduces the excessive use of organic bromides
to near-stoichiometric by promoting the in situ transformation to the
coupling, their advantages include complementary reactivity and
higher cost-efficiency. Nickel-based catalysts are particularly
useful due to their ability to undergo oxidative addition to less
reactive aryl electrophiles such as aryl carboxylates, carbamates,
and nitriles while copper-based catalytic systems are attractive
due to the low cost of precatalysts and ligands used.
As our current project required an easy access to tertiary
cycloalkenylphosphine oxides on
a multi-gram scale, we
corresponding
iodides.
Diarylphosphine
oxides
undergo
searched for a suitable cross-coupling procedure. The literature
survey revealed that available methods for P-cycloalkenylation
are mostly limited to Pd catalysis and include the original Hirao
protocol for H-phosphonates,2 modified protocol for cycloalkenyl
triflates by Holt,12 cycloalkenylation of secondary phosphines
with triflates by Gilbertson,13 cross-coupling between camphenyl
triflate and di(furan-2-yl)phosphine oxide by Knochel,14 Pd-
catalyzed cross-coupling of secondary phosphine-boranes with
triflates and tosylates by Gaumont,15 and a recent work by Yu
featuring Ni/Ru-catalyzed photoredox phosphorylation.16 Related
reactions with non-cyclic alkenyl electrophiles have been
performed using palladium,2,3c,6d nickel,17 cobalt,18 and copper
catalysis.19 To our knowledge there has been no report of
cycloalkenylation with 35‒99% yields and dicyclohexylphosphine
oxide with 30‒53% yields. In the case of acyclic alkenyl bromides
the cross-coupling products undergo conjugate addition of
diphenylphosphine oxide and satisfying yields are observed only for
internal olefins. In the case of aryl bromides satisfying yields
(43‒72%) are observed only for sterically unhindered arenes or
arenes possessing an ortho-directing group. Cycloalkenylphosphine
oxides prepared in the cross-coupling reaction undergo base-
catalyzed and base-promoted conjugate addition to give
bis(phosphinoyl)cycloalkanes.
copper-catalyzed
electrophiles and secondary phosphine oxides so far and such a
reaction could be attractive due to its cost-efficiency.
cross-coupling
between
cycloalkenyl
Introduction
Metal-catalyzed C-P cross-coupling is one of the most versatile
C(sp2)-P bond-forming reactions.1 The original procedure
developed by Hirao for H-phosphonates and aryl/alkenyl halides
in early 1980’s utilized Pd(PPh3)4 as the catalyst and NEt3 as the
base at 90-110 oC under either solvent-free conditions or in
toluene.2 This protocol was shortly proved to work for H-
phosphinates and secondary phosphine oxides in the works of
Xu3 and with slight changes it was also extended to phosphinite-
boranes4 and secondary phosphine-boranes5 by Imamoto and
Gaumont. Major advances have been made in the last 30 years
improving Pd-catalyzed C-P cross-coupling with respect to the
catalyst loading6,7 and scope of organophosphorus6,8 and aryl
coupling partners.9,10 In parallel, with the renaissance of interest
in cheaper transition metal catalysts, analogous nickel-
catalyzed11 and copper-catalyzed19-31,33 C-P cross-coupling
reactions have also been introduced. Although both protocols
often lack the generality and scope of Pd-catalyzed C-P cross-
Cu-catalyzed C-P cross-coupling was first reported in 2003
independently by Buchwald19 and Venkataraman.20 Under
CuI/DMEDA catalysis secondary phosphines underwent efficient
cross-coupling with aryl iodides and dibutyl phosphite reacted
smoothly with aryl iodides and acyclic alkenyl bromides,19
secondary phosphines were also shown to react with aryl
iodides under ligand-free conditions.20 Later, other research
groups expanded the cross-coupling of aryl halides with
secondary phosphines,19‒21,28 H-phosphonates,19,22-24,27
phosphinates22,23,27 and secondary phosphine oxides22‒27 using
L-proline,23 acid,23
pipecolinic N-methylpyrrolidine-2-
carboxamide,24 pyrrolidine-2-phosphonic acid phenyl monoester
(PPAPM),22 (S)-α-phenethylamine,26
and bis-2,6-
,
H-
(methylaminomethyl)pyridine28 as ligands (Scheme 1). In the
case of secondary phosphine oxides high yields are typically
observed only with aryl iodides and electron-deficient aryl
bromides such as 2-bromopyridine,26 however, aryl bromides
1
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10.1002/ejoc.202100456
European Journal of Organic Chemistry
FULL PAPER
possessing ortho-substituents able to coordinate to the metal
center have also been used with some success.21,24,25,27 Non-
activated aryl bromides can be used in reactions with secondary
phosphines.19,28 Under copper catalysis, alkenylphosphorus
compounds have also been accessed via Hirao reduction/cross-
coupling of 1,1-dibromoalkenes,29 decarboxylative cross-
coupling of alkenyl30 and alkynylcarboxylic acids,30,31 and
hydrophosphination of alkynes.32 Dienylphosphine oxides have
also been prepared by Gaumont et al. from dienyl bromides and
secondary phosphine oxides.33
completion we used one of the reagents in excess. Notably, an
excess of Ph2P(O)H caused a dramatic decrease in the
conversion and the higher excess was used, the lower the
efficiency was (Table 1, Entries 5‒6). On the other hand, the use
of two-fold excess of bromocyclohexene gave good results and
both toluene and dioxane proved to be viable solvents (Table 1,
Entries 7 and 9). It must be stressed that the order of the
addition of reactants was a crucial factor and bromocyclohexene
must be added to the catalyst solution first. When
diphenylphosphine oxide was added first, the yields were much
lower (Table 1, Entries 8 and 10).
Table 1. Optimization of cross-coupling conditions.
Entry
DMEDA
[equiv.]
NaI
[equiv.]
1/6a
ratio
Solvent
Conversion
(Yield) [%]
0.1
0.2
0.3
0.4
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
-
1.1
1.1
1.1
1.1
0.8
0.67
2.0
2.0
2.0
1.1
1.1
1.1
1.3
1.1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
15
45
1
2
-
-
51 (50)
25
3
-
-
4
24
5
-
11
6
-
87 (78)
33
7
8[b]
9[a,c]
10[b]
11
12[b]
13[b]
14[d,e]
-
-
84 (73)
12
Scheme 1. Selected copper-catalyzed C-P cross-coupling reactions.
-
1.5
2.0
2.6
1.5
85 (76)
80 (73)
57
Results and Discussion
We started with a model reaction between bromocyclohexene
and diphenylphosphine oxide in a near-stoichiometric ratio using
10 mol% of CuI as the precatalyst, 2.0 equiv. of K2CO3 as the
base and a series of ligands typically used in copper-catalyzed
carbon-heteroatom cross-coupling reactions. Reactions using L-
proline, phenanthroline, α-phenethylamine, TMEDA, and PPh3
all provided only traces of the product and reactions using NHC
ligands, albeit moderately effective, afforded considerable
quantity of α-phosphinoylcyclohexanone as a side product. Initial
experiments revealed that trans-cyclohexane-1,2-diamine
(CyDA) and N,N’-dimethylethylenediamine (DMEDA) were the
most promising, however, with 10 mol% of the ligand the
conversion to the product was only 13% and 15% (Table 1,
Entry 1), respectively.
99 (91)
[a] 2 mmol scale. [b] Inverse addition of reagents to CuI/DMEDA. [c] 0.4 M
concentration. [d] 5 mmol scale. [e] Cs2CO3 was used as the base.
Although the obtained yields were satisfying, the main drawback
was the high excess of the bromide used. Thus, we ventured an
experiment with an in situ transformation of bromocyclohexene
to the presumably more reactive iodocyclohexene. Such an
approach has been effectively realized for aryl bromides by Fu
et al.,22-23 however, the halogen exchange to aryl iodides was
carried out prior to the addition of secondary phosphine oxide
extending the overall reaction time to 40‒48 h. We were pleased
to find that the tandem halogen exchange/cross-coupling
reaction could be carried out concurrently under the conditions
similar to those reported by Klapars and Buchwald for
bromine/iodine exchange in aryl bromides.34 The use of 1.5
By gradually increasing the amount of DMEDA from 10 mol% to
30 mol% we were able to increase the yield to 50%, however,
further increase to 40 mol% of the ligand led to lower conversion
(Table 1, Entries 2‒4). In order to push the reaction to
2
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10.1002/ejoc.202100456
European Journal of Organic Chemistry
FULL PAPER
equiv. of NaI additive and slight excess of bromocyclohexene
(1.1 equiv.) in dioxane as the solvent provided equally high yield
of the product as the reaction with 2.0 equiv. of bromide and no
additive (Table 1, Entry 11). Moreover, in the presence of NaI
the reaction was much less sensitive to the reactant addition
order (Entry 12), however, high excess of NaI was also
detrimental to the reaction yield (Entry 13). Finally, changing the
base from K2CO3 to Cs2CO3 provided full conversion of
secondary phosphine oxide and 91% isolated yield of the
product (Entry 14). Both the high temperature and Cu(I) as a
precatalyst were found to be necessary as lowering the reaction
With the optimized conditions in hand we ran a scope screening
with different bromocycloalkenes and secondary phosphine
oxides (Table 2). Diarylphosphine oxides with o-tolyl, p-tolyl, o-
anisyl, 1-naphthyl, and 3,5-di-tert-butylphenyl aryl substituents
exhibited comparable reactivity to diphenylphosphine oxide in
the reactions with bromocyclohexene affording products 7b-f in
84-89%. Lower yields (64-65%) were observed for phenyl(tert-
butyl)phosphine oxide 7h and bis(4-fluorophenyl)phosphine
oxide
7i.
The
most
problematic
substrate
was
dicyclohexylphosphine oxide which afforded the cross-coupling
product 7g in only 30%, a small increase in the yield to 36% was
achieved with DMCyDA (trans-N,N’-dimethylcyclohexane-1,2-
diamine) as the ligand. Bromocycloheptene showed similar
behavior to bromocyclohexene in the reactions with
diarylphosphine oxides affording cycloheptenylphosphine oxides
8a,b,d in 86-99%, however, it performed more efficiently in the
reaction with dicyclohexylphosphine oxide affording 8g in 53%
yield.
o
temperature to 80 C and changing the precatalyst to Cu(OTf)2
led to only traces of the product.
Table 2. Scope screening for copper-catalyzed C-P bond formation.
Interestingly, under the optimized conditions bromocyclopentene
reacted efficiently with di-o-anisylphosphine oxide to give the
product 9d in 87%, but reacted poorly with diphenylphosphine
oxide affording only traces of the cross-coupling product 9a
along with 17% of bis(diphenylphosphinoyl)cyclopentane 25
which must have been formed through conjugate addition of
secondary phosphine oxide to the cross-coupling product. This
different behavior may be related to the scale of the reaction as
a similar problem was encountered for the reaction of 1-
bromocyclohexene at the scale of 1 mmol or less (see the
discussion on the role of NaI additive). In this case, the less
soluble base K2CO3 was much more efficient and produced the
cross-coupling product 9a selectively in 84% yield. Similarly,
K2CO3 was more efficient for a mixture of isomeric 2-methyl- and
6-methyl-1-bromocyclohex-1-enes (62:38 ratio) providing two
products 10a and 10a’ (85:15 ratio) in 41% overall yield
compared to 30% (77:23 ratio) using Cs2CO3.
Scheme
2.
Cross-coupling/conjugate
addition
of
4-bromo-1,2-
dihydronaphthalene.
The reaction of diphenylphosphine oxide with 4-bromo-1,2-
dihydronaphthalene afforded the conjugate addition product,
1,2-bis(diphenylphosphinoyl)tetralin, 11 as the major product
(45% isolated yield) and only traces of the cross-coupling
product were detected in a mixed fraction of side products after
column chromatography (Scheme 2). A reaction with either 50%
excess of 4-bromo-1,2-dihydronaphthalene or a reaction with 2.0
equiv. of diphenylphosphine oxide provided inferior results.
We tested our model reaction between diphenylphosphine oxide
and bromocyclohexene on a 10 mmol scale to see if this method
can be used for preparative purposes to obtain higher quantities
of cycloalkenylphosphine oxides. Two separate runs afforded
the product in 83% and 86% yield respectively (Scheme 3).
Isolated yields are given. Reaction conditions: R2P(O)H (1 mmol),
bromoalkene (1.1 mmol), CuI (0.1 mmol), DMEDA (0.3 mmol), Cs2CO3 (2
mmol), NaI (1.5 mmol), dioxane (0.2 M), 110 oC, 20 h. [a] 5 mmol scale.
[b] K2CO3 was used as the base instead of Cs2CO3. [c] a 62:38 mixture of 2-
methyl- and 6-methyl-1-bromocyclohexenes was used, 6-methyl analogue 10a’
was obtained as the minor product in 6%. [d] DMCyDA was used as the ligand
instead of DMEDA. [e] 0.5 mmol scale.
3
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10.1002/ejoc.202100456
European Journal of Organic Chemistry
FULL PAPER
and 30% yields, respectively (Table 4, Entries 1 and 2). In the
case
of
more
hindered
1-bromo-2-methylprop-1-ene,
alkenyldiphenylphosphine oxide 14 was obtained in 85% yield
along with small amounts of isomerized 2-methylallylphosphine
oxide 14a and conjugate addition product 17 which was not
isolated (Entry 3). Tetrasubstituted olefin 2-bromo-3-methylbut-
2-ene afforded the tertiary phosphine oxide 15 as the only
product in 75% yield (Entry 4). Cs2CO3 was unsuitable as the
base, tested for the reactions with 2-bromopropene and 1-
bromo-2-methylprop-1-ene it only led to small amounts of
conjugate addition products (27% and 14% respectively) with no
cross-coupling products.
Scheme 3. Gram-scale synthesis of 7a.
Phosphonates as a general class of compounds find wide
application in different fields of industry and cross-coupling of H-
phosphonates with aryl halides is arguably the most well
researched C-P cross-coupling reaction in organophosphorus
chemistry. No protocol for Cu-catalyzed cycloalkenylation of H-
phosphonates has been reported to date. Thus, we were
interested if our method could be applied to dialkyl phosphites
(Table 3).
Table 4. Cross-coupling of non-cyclic alkenyl bromides.[a]
Table 3. Cycloalkenylation of dialkyl phosphites.
Isolated yields are given. [a] K2CO3 was used as the base. [b] The reaction
was carried out in toluene using 2.0 equiv. of the bromide, K2CO3 as the base
and no NaI additive.
The method did not prove to be general for dialkyl phosphites as
only 1-bromocycloheptene reacted satisfyingly with diisopropyl
phosphite to give 8k in 69% yield, 1-bromocyclopentene and 1-
bromocyclohexene gave poor yields of 9k and 7k (28-30%) and
diethyl phosphite gave the appropriate product 7j in an even
lower yield. Considerably better results were obtained by using
2.0 equiv. of 1-bromocyclohexene along with K2CO3 as the base
and no iodide additive. It is worth noting, however, that in all
cases the conversions as calculated from 31P NMR spectra of
the reaction mixtures after 20 h were in the range of 84-98% and
the weight of the post-reaction mixtures was much lower than
expected which could be due to undesired dealkylation reaction
producing insoluble species.
Next we tested our concurrent tandem halogen exchange/cross-
coupling protocol in reactions with acyclic alkenyl bromides
possessing a varying degree of substitution (Table 4). In all
cases full or nearly full conversion of diphenylphosphine oxide
was observed with K2CO3 as the base. In the case of the
reactions with 2-bromopropene and trans-1-bromopropene, the
cross-coupling products 12 and 13 underwent conjugate addition
to a considerable degree affording diphosphine dioxide 16 in 40
[a] Conversions based on 31P NMR spectra of post-reaction mixtures, isolated
yields are given in parentheses.
Excluding 2-bromopyridine and aryl bromides with ortho-
directing groups, the existing protocols for Cu-catalyzed
arylation of secondary phosphine oxides are efficient only for
aryl iodides. Previously reported halogen exchange/cross-
coupling reactions with aryl bromides required halogen
exchange to be performed before the addition of R2P(O)H. Thus,
we were also curious if our concurrent tandem halogen
exchange/cross-coupling method could be extended to aryl
bromides.
The reactions of diphenylphosphine oxide with a set of both
electron-rich and electron-poor aryl bromides with a varying
degree of steric hindrance exemplify that electron density of aryl
ring exerts a small to moderate effect on the efficiency of
transformation while steric effects have a high impact (Table 5).
As in the case of acyclic alkenyl bromides, the choice of K2CO3
as the base was crucial, no cross-coupling took place between
4
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10.1002/ejoc.202100456
European Journal of Organic Chemistry
FULL PAPER
diphenylphosphine oxide and 2-bromotoluene or 1-
bromonaphthalene when Cs2CO3 was used. With K2CO3, the
reaction with o-bromotoluene showed only 10% conversion to 21.
Replacing DMEDA with DMCyDA as the ligand afforded the
product with slightly higher conversion, thus we opted to use the
latter for other aryl bromides. The reaction of 6a with 1-
bromonaphthalene led to a moderate yield of the cross-coupling
product 20 (34%). On the other hand, the reactions with non-
observed for 3-bromotoluene (19% vs. 77% under the optimized
conditions).
hindered
3-bromotoluene
and
1-bromo-4-
(trifluoromethyl)benzene afforded the products 18 and 19 with
69% and 72% yield, respectively. Notably, the cross-coupling of
sterically hindered and electron-rich 2-bromoanisole furnished
the product 22 with a comparable yield (71%). Similarly, even
more electron-rich 2-bromoaniline provided the product 23 with a
significantly higher yield (43%) than 2-bromotoluene, which can
be attributed to the ability of methoxy and amino groups to act
as directing groups.
Table 5. Cross-coupling of aryl bromides.[a]
Scheme 4. Control reactions with CuBr as the precatalyst.
The post-reaction mixtures of cross-coupling between 1-
bromocyclohexene and diphenylphosphine oxide catalyzed by
CuI, with and without NaI additive, contained both unreacted
cycloalkenyl bromide as well as the corresponding iodide. A
control reaction under the optimized cross-coupling conditions
without secondary phosphine oxide led to full conversion of 1-
bromocyclohexene and provided 1-iodocyclohexene in 99%
1
yield by GC-MS analysis and in 67% after work-up by H NMR
against hexadecane as an internal standard (Scheme 5).
[a] Conversions based on 31P NMR spectra of post-reaction mixtures, isolated
yields are given in parentheses.
Regarding the role of NaI additive, we carried out control cross-
coupling reactions for 1-bromocyclohexene, 1-bromo-2-
methylpropene and 3-bromotoluene with CuBr as the precatalyst
in place of CuI and in the absence of NaI (Scheme 4). The
reaction with 2.0 equiv. of 1-bromocyclohexene afforded the
cross-coupling product in 41%. This is considerably lower than
the analogous reaction (2.0 equiv. of the bromide, K2CO3, no
NaI) with CuI which provided 84% of the product. In stark
contrast to the reaction with CuI and NaI additive, Cs2CO3 as the
base had a dramatically negative impact on cycloalkenylation
with CuBr. The control reaction with 1-bromo-2-methylpropene
was also less effective (47% of the cross-coupling product vs.
89% under the optimized conditions), however, nearly full
conversion of Ph2P(O)H was observed and a considerable
amount of the conjugate addition product was formed (37% vs.
5% under the optimized conditions). Much lower yield was also
Scheme 5.Halogen exchange of 1-bromocyclohexene.
In order to compare the rate of the halogen exchange and the
cross-coupling, the model reaction was stopped after 1 hour and
the reaction mixture was analyzed by GC-MS and NMR. At this
point the ratio of 1-iodocyclohexene and 1-bromocyclohexene
was 97:3 while the NMR yield of the cross-coupling product was
14% (Scheme 6). These results indicate that NaI additive
promotes the halogen exchange of organic bromides to the
5
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10.1002/ejoc.202100456
European Journal of Organic Chemistry
FULL PAPER
corresponding iodides and this reaction is considerably faster
than the cross-coupling.
Scheme 6. Halogen exchange/cross-coupling after 1 hour.
A kinetic study of the model reaction was inconclusive and
hinted that the course of the reaction may be sensitive to the
scale. For the reaction at 1 mmol scale after 1 hour almost all 1-
bromocyclohexene was transformed into 1-iodocyclohexene by
GC-MS, however, there was no cross-coupling product formed
at this point. After 2 hours the conversion to 7a was 29% but
after 3 hours the proportion of 7a in the reaction mixture started
decreasing and the formation of the conjugate addition product
was observed. After 24 h the overall conversion of Ph2P(O)H
was 58% and the yields of the cross-coupling and conjugate
addition products were 12% and 46% respectively while no 1-
iodocyclohexene was detected by GC-MS and no alkene
degradation product of 1-iodocyclohexene was present. A set of
4 reactions run at 0.5 mmol scale and stopped after 1, 2, 3 and
20 hours had a similar progress although they were slower and
the final yields of the cross-coupling and conjugate addition
products were 15% and 12% respectively (see Supporting
Information). This is in contrast to the reactions run at 5 mmol
and 10 mmol scale which showed ≤1% conjugate addition. A
similar problem of different reactivity at 1 mmol scale when
Cs2CO3 was used as the base might be present for 1-
bromocyclopentene for which K2CO3 turned out to be optimal
(Table 2).
Scheme 7. Proposed catalytic cycle.
Based on the obtained results and previous studies published in
the literature35 we propose the catalytic cycle for copper-
catalyzed tandem halogen exchange/C-P cross-coupling as
depicted in Scheme 7. (Diamine)CuI complex I readily formed
from CuI and DMEDA or DMCyDA catalyzes two reactions.
Firstly, in the halogen exchange cycle it reacts with alkenyl or
aryl bromide to furnish the corresponding iodide and
(diamine)CuBr complex VI (1b) which is reverted back to
(diamine)CuI I in the reaction with NaI (2b). Then in the cross-
coupling cycle, (diamine)CuI I reacts with R2P(O)H to form
(diamine)Cu-P(O)R2 complex II through base-mediated halide
substitution (1a). The next step is an oxidative addition of
complex II to an organic iodide forming Cu(III) complex III (2a)
from which the product is released reinstating the catalyst (3a).
The optimization study revealed that excess diphenylphosphine
oxide is detrimental for the cross-coupling yield. This and the
positive impact of excess diamine in relation to copper suggest
the involvement of an equilibrium between different copper(I)
species
including
some
deactivated
or inactive phosphorylcopper complex akin to bis(amidate)- and
Table 6. Optimization of conjugate addition to cyclohexenylphosphine oxide 7a.
Entry
1
CuX
Ligand
Base
LiOt-Bu (0.2)
Solvent
toluene
Yield [%]
85[b]
-
-
2
-
-
LiOt-Bu (0.2)
dioxane
dioxane
toluene
toluene
toluene
87[c]
97[c]
<5[a]
<5[a]
70[c]
3[d]
4[e]
5[e]
6
-
-
Cs2CO3 (2.0)
CuOt-Bu (0.1)
CuOt-Bu (0.1)
CuI (0.1)
dppbz (0.12)
(S)-MonoPhos (0.2)
dppp (0.1)
-
-
LiOt-Bu (0.2)
[a] Yield based on 31P NMR spectrum of reaction mixture after 20 h. [b] Yield based on 31P NMR spectrum of post-work-up mixture. [c] Isolated yield. [d] 1.1 equiv.
Ph2P(O)H was used. [e] CuOt-Bu was generated in situ from CuPF6(MeCN)4 and LiOt-Bu.
6
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10.1002/ejoc.202100456
European Journal of Organic Chemistry
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bis(imidate)cuprates which have been reported to be much less
active than neutral monoamidate copper complexes in C-N
cross-coupling.36
between cycloalkenyl bromides and secondary phosphine
oxides. The method works well for unsubstituted 1-
bromocycloalkenes and tolerates
a
broad scope of
According to the control cross-coupling reactions from Scheme 4, diarylphosphine oxides (65-99% yield). The reaction is less
alkenyl and aryl bromides are reactive on their own, however,
the cross-coupling was much less efficient when CuBr was used
rather than CuI. With the latter the transformation efficiency is
likely increased through halogen exchange and cross-coupling
of the formed iodides. Since iodide salt is formed in the base-
mediated nucleophilic substitution, NaI additive is not required
for halogen exchange. However, the addition of NaI may further
improve the efficiency of the cross-coupling by shifting the
equilibrium towards the species active in halogen exchange and
limiting the formation of inactivated phosphorylcopper species.
As shown by Bunlaksananusorn and Knochel secondary
phosphine oxides can undergo base-catalyzed conjugate
addition to cycloalkenylphosphine oxides with KOt-Bu as the
base and DMSO as the solvent.37 We found that the reaction of
cyclohexenylphosphine oxide 7a and diphenylphosphine oxide
6a could also be run in non-polar solvents such as dioxane and
toluene using LiOt-Bu as the catalytic base (Table 6, Entries 1-2)
or even using excess Cs2CO3 (Table 6, Entry 3). We were
interested if this reaction could be made stereoselective by using
a chiral copper(I) complex which could open up a path towards
one-pot cross-coupling/conjugate addition process. However,
effective when alkyl substituents are introduced at the
phosphorus atom in secondary phosphine oxides (30-64%) or
sterically hindered bromocycloalkenes are used. In the case of
the activated cyclic bromide, 4-bromo-1,2-dihydronaphthalene,
the conjugate addition product is the major product and only
traces of the cross-coupling product are observed. The
presented method can also be applied to selected acyclic
alkenyl bromides and aryl bromides. However, in the case of
non-hindered vinylic bromides undesired conjugate addition to
the cross-coupling products considerably lowers the yield.
Among aryl bromides, only sterically non-hindered substrates
and those possessing ortho-directing groups undergo the cross-
coupling reaction with moderate to good yields (43-72%).
Cycloalkenyldiphenylphosphine oxides obtained with the
presented
method
were
transformed
into
bis(phosphinoyl)cycloalkanes in base-catalyzed conjugate
addition which highlights their potential importance as
intermediates for the synthesis of bis(phosphino)cycloalkanes
and related ligands. Further work on expanding this method to
asymmetric variants is currently underway in our laboratory.
preliminary results showed that in situ generated CuOt-Bu Conflicts of interest
complexes were not suitable as catalysts for this transformation
(Table 6, Entries 4-5), while the reaction in the presence of extra
LiOt-Bu did provide the desired product albeit with lower yield
than the reaction without copper(I) salt (Table 6, Entry 6).
There are no conflicts to declare.
Acknowledgements
The authors acknowledge the financial support from the Polish
Ministry of Science and Higher Education (research project no.
DI 2017 012247).
Table 7. Base-catalyzed secondary phosphine oxide addition to
cycloalkenylphosphine oxides.
Keywords: catalysis • copper • cross-coupling • halogen
exchange • organophosphorus
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8
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Entry for the Table of Contents
A protocol for copper-catalyzed halogen exchange/C-P cross-coupling between (cyclo)alkenyl/aryl bromides and secondary
phosphine oxides has been developed. The addition of sodium iodide increases the yield of the cross-coupling by promoting in situ
halogen exchange of organic bromides to the corresponding iodides.
9
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