Rhodium-catalyzed oxidative C-H activation/cyclization for the synthesis of phosphaisocoumarins and phosphorous 2-pyrones

Article abstract of DOI:10.1002/chem.201302652

Rhodium-catalyzed cyclization of phosphinic acids and phosphonic monoesters with alkynes has been developed. The oxidative annulation proceeds with complete conversion of phosphinic acid derivatives and allowed the atom-economic preparation of useful phosphaisocoumarins with high yield and selectivity. The reaction is tolerant of extensive substitution on the phosphinic acid, phosphonic monoester and alkyne, including halides, ketone, and hydroxyl groups as substituents. Furthermore, we found that alkenylphosphonic monoesters proceed to give a wide range of phosphorus 2-pyrones through oxidative annulation with alkynes. Mechanistic studies revealed that Ci￡H bond metalation was the rate-limiting step. Copyright

Full text of DOI:10.1002/chem.201302652

FULL PAPER
DOI: 10.1002/chem.201302652
Rhodium-Catalyzed Oxidative C–H Activation/Cyclization for the Synthesis
of Phosphaisocoumarins and Phosphorous 2-Pyrones
Youngchul Park, Jungmin Seo, Sangjune Park, Eun Jeong Yoo, and Phil Ho Lee*[a]
Dedicated to Professor Han-Young Kang on the occasion of his 60th birthday
Abstract: Rhodium-catalyzed cycliza-
tion of phosphinic acids and phosphon-
ic monoesters with alkynes has been
developed. The oxidative annulation
proceeds with complete conversion of
phosphinic acid derivatives and al-
lowed the atom-economic preparation
of useful phosphaisocoumarins with
high yield and selectivity. The reaction
is tolerant of extensive substitution on
the phosphinic acid, phosphonic mono-
ester and alkyne, including halides,
ketone, and hydroxyl groups as sub-
stituents. Furthermore, we found that
alkenylphosphonic monoesters proceed
to give a wide range of phosphorus 2-
pyrones through oxidative annulation
with alkynes. Mechanistic studies re-
À
vealed that C H bond metalation was
Keywords: alkynes · annulation ·
the rate-limiting step.
À
C H activation · cyclization · phos-
phorous heterocycles · rhodium
Introduction
activated alkyne after Sonogashira coupling reaction of aryl-
phosphate[8] or arylphosphinic acid[9] [Scheme 1, Eq. (1)].
Organophosphorus compounds continue to receive wide-
spread attention because of their ubiquity in biological sys-
tems[1] and because of their vital role as bioisosteres of car-
boxylate moieties.[2] Given the prevalence of phosphorus
compounds in medicinal chemistry and pharmaceutical in-
dustries,[3] both the design of new structures of phosphorus
compounds and their applications have been explored. Re-
cently, Kim and our group disclosed various transition-
À
metal-catalyzed C H functionalizations by using phospho-
ryl-related compounds as a directing group[4] in an effort to
pioneer a new direct synthetic method for introducing struc-
tural variation into phosphorous compounds.[5] Moreover, by
understanding the unique properties of phosphorous func-
tional groups based on several references to the ortho-met-
alation of aryl-phosphoryl moieties,[6] a novel protocol for
Scheme 1. Previous synthetic routes to phosphaisocoumarins.
À
the C H alkenylation of monophosphoric acid and benzylic
phosphonic monoesters was developed.[4c,g]
Although less studied, the preparation of phosphaisocou-
marins, which are isocoumarin phosphorus analogues, has
also continued to be in strong demand because of their in-
teresting biological properties.[3a,7] Ding and Peng have pre-
pared phosphaisocoumarins through intramolecular nucleo-
philic attack by the oxygen of the phosphonyl group on the
In contrast to usual multistep syntheses [such as
Scheme 1, Eq. (1)], economically more attractive routes that
À
proceed through cleavage of C H bonds, allows the organic
syntheses to be streamlined and minimizes byproduct forma-
tion.[10] In a continuation of our studies of C H bond activa-
À
tion reactions,[11] we recently developed a rhodium-catalyzed
À
C H cyclization of phosphonic acid monoester for the prep-
aration of phosphaisocoumarins [Scheme 1, Eq. (2)].[4d,12]
Although the reactions appear to represent a highly effi-
cient and selective process, this approach is still in its infan-
cy from the synthetic point of view, in that substrate scope is
[a] Y. Park, J. Seo, S. Park, Prof. Dr. E. J. Yoo, Prof. Dr. P. H. Lee
Department of Chemistry
Kangwon National University
Chuncheon 200-701 (Republic of Korea)
Fax : (+82)33-253-7582
À
limited. At the present time, for instance, C H annulation
of phosphinic acid with dialkyl-substituted alkynes or elec-
tron-deficient diaryl-substituted alkynes remain largely unin-
vestigated. We therefore became interested in exploring the
E-mail: phlee@kangwon.ac.kr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302652.
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16461

À
effective C H activation/cyclization of phosphinic acid de-
was obtained in 87% yield. An advantage of the present re-
actions was demonstrated by the direct cyclization of both
electron-rich and electron-deficient substrates 1, giving the
corresponding products 2d–f. Reaction of sterically bulky
substrate, bis(2,3-dimethylphenyl)phosphinic acid, with dec-
5-yne also produced the cyclized product 2g in 89% yield.
The phosphinic acid derivative bearing a 1-naphthalenyl
group also worked well, resulting in the formation of 2h in
85% yield. Moreover, annulation of di(thiophen-2-yl)phos-
phinic acid in tBuOH afforded the desired product 2i in
rivatives with broadly expanded alkyne reagents. We wish to
report the results of these investigations herein.
Encouraged by the our previous results,[4b] the most effi-
cient catalysis was achieved with alkenylphosphonic mono-
esters, which also allowed the synthesis of phosphorus 2-py-
rones (Scheme 2).
À
73% yield. Unsymmetrical internal alkyne promoted the C
H activation followed by cyclization, thus producing 2j with
high regioselectivity. We were also pleased to obtain a single
product 2k in 87% yield when mesitylACTHNUTRGNEUNG(phenyl)phosphinic
acid reacted with hex-3-yne under the reaction conditions.
Use of Ag2CO3 and AgOAc as the co-oxidant system was
found to be crucial for efficient annulation of arylphosphinic
acid derivatives with electron-deficient diaryl-substituted
ethynes such as bis(3-chlorophenyl)ethyne or bis(3-bromo-
phenyl)ethyne, although the terminal alkyne did not react
with phophinic acid under the optimized reaction condi-
tions.
Scheme 2. New synthetic routes to phosphaisocoumarins and phosphorus
À
2-pyrones through rhodium-catalyzed C H activation/cyclization.
Results and Discussion
Annulation of phosphonic monoesters with alkynes: We
became interested in the use of phosphonic monoester di-
recting groups for a single-step phosphaisocoumarin synthe-
À
C H cyclization of phosphinic acid with dialkyl-substituted
À
alkynes: Almost all known C H activated annulations of
À
phosphinic acids proceed with diaryl-substituted alkynes.
sis through C H bond functionalization. In contrast to pio-
Thus, the preparation of 3,4-dialkyl-substituted phosphaiso-
neering works, a protocol for cyclization of phosphonic
À
coumarin 2 through C H acti-
vation has been accomplished
by employing phosphinic acid
1
and dialkyl-substituted al-
kynes (Scheme 3). This highly
À
attractive C H annulation of
phosphinic acid 1 with dialkyl-
substituted alkynes was realized
even
more
successfully,
when commercially available
[{Cp*RhCl2}2] (2 mol%) was
applied as the catalyst. The use
of Ag2CO3 and AgOAc as co-
oxidant with phosphinic acid
1 in tBuOH proved viable.
The developed annulation re-
action with dialkyl-substituted
alkynes tolerated a wide variety
of phosphinic acids with
a range of functional groups.
Diphenylphosphinic acid (1a)
reacted with each counterpart
alkyne smoothly, producing the
desired
phosphaisocoumarins
2a and 2b in 93 and 86% yield,
respectively. When substrate
1c, having an ortho-methyl
group on the phenyl ring, was
Scheme 3. Rh-catalyzed annulation reactions of phosphinic acids with dialkyl-substituted alkynes. Reagents
and conditions:
1 (0.15 mmol), 4 (0.23 mmol), [{Cp*RhCl2}2] (2 mol%), Ag2CO3 (0.15 mmol), AgOAc
annulated with hex-3-yne, 2c (0.15 mmol), tBuOH (1 mL), 908C, 16 h. Numbers in parentheses indicate isomeric ratio.
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Phosphaisocoumarins and Phosphorous 2-Pyrones
FULL PAPER
monoesters gave the phosphaisocoumarins with an alkoxy
group on phosphorus; such compounds are readily trans-
formed into useful functional groups including the hydroxyl
group.
We initiated our studies by exploring the use of additives
and solvents for the catalytic annulation of 1,2-diphenyl-
ACHTUNGTRENNUNGethyne (4a) by ethyl phenylphosphonic monoester (3a).
Similar tendencies were observed under the optimum reac-
tion conditions to that of annulation of phosphinic acid,
which are summarized in Table 1. The use of AgSbF6 and
[a]
À
Table 1. Optimization of C H annulation.
Entry
Additive
(equiv)
Solvent
Yield
[%][b]
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
8
none
AgSbF6 (0.5)
AgBF4 (0.5)
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tAmOH
1,4-dioxane
0
0
0
À
Scheme 4. Rh-catalyzed C H annulation of ethyl phenylphosphonic
monoester with various alkynes. Reagents and conditions: 3a
(0.15 mmol),
(0.15 mmol), AgOAc (0.15 mmol), tBuOH (1 mL), 908C. Numbers in pa-
rentheses indicate isomeric ratio. [a] 3a (1.0 mmol), (1.5 mmol),
4
(0.23 mmol), [{Cp*RhCl2}2] (2 mol%), Ag2CO3
.
Cu
N
23
45
57
49
81
90
68
49
AgOAc (0.5)
Ag2CO3 (0.5)
Ag2CO3 (0.5)/CuACHTNUGTRNEUNG(OAc)2 H2O (0.5)
Ag2CO3 (0.5)/AgOAc (0.5)
Ag2CO3 (1)/AgOAc (1)
Ag2CO3 (1)/AgOAc (1)
Ag2CO3 (1)/AgOAc (1)
4
[{Cp*RhCl2}2] (2 mol%), Ag2CO3 (1.0 mmol), AgOAc (1.0 mmol),
tBuOH (6.7 mL), 908C, 16 h.
.
9
10
11
was performed on 1.0 mmol scale without encountering
problems, thereby delivering 5a in excellent yield.
Notably, electron-deficient (thus deactivated for an oxida-
tive coupling) bis(3-chlorophenyl)ethyne was effectively
converted, generating 5e in 70% yield, although longer re-
action time was required. Dialkyl-substituted alkynes were
converted with high yields, furnishing the desired phosphai-
socoumarins 5 f and 5g, as did diaryl-substituted alkynes.
The unsymmetrical disubstituted alkynes could be em-
ployed, giving a unique reactivity, thereby illustrating the
practicalities of the developed reaction. Various unsymmet-
rical alkyne substrates provided the desired product 5h–k in
high yields, and 5h and 5i were predominantly produced
with high regioselectivity. However, unfortunately, only low
site selectivity of products 5j and 5k was observed.
To establish the synthetic versatility, we probed the scope
of the reaction with arylphosphonic monoesters containing
useful functional groups with internal alkynes (Table 2).
Substrates with a halogen atom gave the corresponding
products in high yields (Table 2, entries 1–3). Indeed, para-
fluoro substituted substrate reacted with unsymmetrically
substituted alkyne with high regioselectivity, providing phos-
phaisocoumarin 6b. The substrate scope of this reaction was
found to be remarkably broad in terms of tolerance towards
a strongly electron-withdrawing acetyl group on the aryl
ring (Table 2, entry 4). Annulation of electron-rich sub-
strates afforded phosphaisocoumarins 6e–j in 85–95% iso-
lated yields (Table 2, entries 5–10). It should be mentioned
that valuable functional groups such as a free hydroxyl
group was completely tolerated under the present reaction
conditions (Table 2, entry 11). Ethyl naphthalen-1-ylphos-
[a] Reaction conditions: 3a (0.15 mmol), 4a (0.23 mmol), [{Cp*RhCl2}2]
(2 mol%), additive, solvent (1 mL), 908C, 16 h. [b] Yield of isolated
product.
AgBF4, which are known to positively influence Rh-cata-
À
lyzed C H functionalization reactions, was tested; however,
these systems proved to be incompatible with the cyclization
of 3a with alkyne 4a (Table 1, entries 2 and 3). Interestingly,
the use of AgOAc (0.5 equiv) or Ag2CO3 (0.5 equiv) was
found to be efficient, provided that reactions were conduct-
ed under air, whereas copper salts showed low reactivity
(Table 1, entries 4–6). Further screening of the oxidant re-
vealed that the addition of Ag2CO3/AgOAc (0.5 equiv each)
as a co-oxidant dramatically improved the conversion to
over 80% in tBuOH (Table 1, entry 8). Surprisingly, the best
yield (90%) was obtained under identical reaction condi-
tions of annulation of phosphinic acid with alkyne by using
a stoichiometric amount of Ag2CO3 and AgOAc together
(Table 1, entry 9). The attempted synthesis of phosphaiso-
coumarins in tAmOH or 1,4-dioxane occurred less efficient-
ly (Table 1, entries 10 and 11).
À
We next explored the scope of the Rh-catalyzed C H an-
nulation with internal alkynes, including unsymmetrical dis-
ubstituted alkynes 4, by using the optimized catalytic condi-
tions (Scheme 4). Reaction of ethyl phenylphosphonic
monoester (3a) with various diaryl-substituted alkynes pro-
ceeded smoothly to provide the desired products 5a–d in
good to excellent yields. Synthesis of phosphaisocoumarin
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16463

P. H. Lee et al.
À
Table 2. Substrate scope for C H annulation of arylphosphonic monoest-
ers with alkynes.[a,b]
Entry R1
R2
R3
Time
[h]
6
Yield
[%]
1
2
4-F
4-F
Ph
Me
Ph
Ph
16
5
6a 82
6b 84 (10:1)
3
4
5
6
7
8
9
10
11
12
13
4-I
N
G
6c
6d 78
6e 92
86
Scheme 5. Rhodium-catalyzed oxidative cyclization of phosphonic mono-
esters with alkyne.
4-Ac
2-Me
2-Me
3-Me
3-Me
6f
95 (10:1)
6g 86
6h 85 (8.8:1)
6i
6j
6k 76
6l 89
6m 82 (10:1)
4-MeO Ph
4-MeO Me
93
90 (6.7:1)
4-OH
[c]
[c]
[a] Reaction conditions:
3
(0.15 mmol), 4 (0.23 mmol), [{Cp*RhCl2}2]
(2 mol%), Ag2CO3 (0.15 mmol), AgOAc (0.15 mmol), tBuOH (1 mL),
908C. [b] Numbers in parentheses indicate isomeric ratio. [c] Ethyl naph-
thalen-1-ylphosphonic monoester was used as substrate 3.
phonic monoester gave the cyclic compounds 6l and 6m
with high yields and selectivities (Table 2, entries 12 and 13).
This method was also effective for the direct annulation
of substrates containing heterocyclic moieties, such as ethyl
1H-indol-2-ylphosphonic monoester and ethyl thiophen-2-yl-
phosphonic monoester (Scheme 5).
Surprisingly, the para-carboxylic acid substituted phenyl-
phosphonic monoester smoothly cyclized with internal al-
kynes to give 6p and 6q in 62 and 59% yield, respectively
[Eq. (5)].
À
Scheme 6. Rh-catalyzed C H annulation of arylphosphonic monoesters
with dialkyl-substituted alkynes. Reagents and conditions: 3 (0.15 mmol),
4 (0.23 mmol), [{Cp*RhCl2}2] (2 mol%), Ag2CO3 (0.15 mmol), AgOAc
(0.15 mmol), tBuOH (1 mL), 908C.
90% yield, whereas most substrates underwent rhodium-cat-
alyzed cyclization regioselectively at the sterically less hin-
dered reaction site. Although the the reasons behind the ob-
served selectivity remain unclear at this stage, one plausible
explanation is that coordination of the 3-oxy could partici-
À
There was little difference in reactivity between diaryl
and dialkyl substituted alkynes (Scheme 6). A variety of ar-
ylphosphonic monoesters, with meta- or para-substituents,
furnished the desired products 7a and 7b, respectively, with
excellent yields. The catalytic system proved to be broadly
applicable and was found to be tolerant of electron-with-
drawing functional groups such as iodo, fluoro and ketone
substituents (7c–e). Exposure of naphthalen-1-ylphosphonic
monoester with hex-3-yne in the presence of [{Cp*RhCl2}2]
catalyst led to the formation of phosphaisocoumarin 7 f in
82% yield.
pate in C H activation of the C2 reaction site.
As a consequence of the application of our novel step-
economical strategy for annulation, we wished to develop
a direct synthetic method to generate phosphorus 2-pyrones
by using the cyclization reaction of alkenylphosphonic
monoesters with alkynes. Gratifyingly, the envisioned direct
reaction for the formation of phosphorus 2-pyrones occurred
readily with alkenylphosphonic monoester to give the corre-
sponding phosphorus 2-pyrones (Table 3). When the estab-
lished reaction conditions (Ag2CO3 and AgOAc as co-oxi-
dant in tBuOH at 1208C) were applied to cyclization of 8a,
product 9a was obtained in 21% yield (Table 3, entry 1).
Employing Ag2CO3 as the sole oxidant with 2 mol%
[{Cp*RhCl2}2] gave desired product in 19% yield, which re-
À
Unexpectedly, C H activation of 3,4-(methylenedioxy)-
phenylphosphonic monoester occurred at C2 instead of the
sterically less hindered C6 position to afford product 7g in
16464
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Phosphaisocoumarins and Phosphorous 2-Pyrones
FULL PAPER
Table 3. Optimization studies for the formation of phosphorus 2-pyrones
[a]
À
through C H functionalization.
Entry
Oxidant
(equiv)
Solvent
Yield
[%][b]
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
8
9
Ag2CO3 (1)/AgOAc (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
tBuOH
tBuOH
toluene
C6H5Cl
tAmOH
DMF
DMF
DMF
DMF
21
19
30
68
65
75
0
Ag2CO3 (1)
Ag2O (1)
Cu
N
25
82
Ag2CO3 (2)
[a] Reaction conditions: 8a (0.15 mmol), 4a (0.23 mmol), [{Cp*RhCl2}2]
(2 mol%), oxidant, solvent (1 mL), 1208C, 10 h under N2. [b] Determined
1
by H NMR spectroscopic analysis of the crude products using CH2Br2 as
internal standard.
vealed that there was no significant difference between co-
oxidant Ag2CO3/AgOAc and single Ag2CO3 (Table 3,
entry 2). After surveying a wide array of organic solvents,
we observed that the use of N,N-dimethylformamide (DMF)
gave the best reactivity (Table 3, entries 2–6). Attempted
rhodium-catalyzed annulation with other oxidants such as
Scheme 7. Rh-catalyzed annulations of alkenylphosphonic esters with al-
kynes. Reagents and conditions:
8
(0.15 mmol),
4
(0.23 mmol),
[{Cp*RhCl2}2] (2 mol%), Ag2CO3 (1 equiv), DMF (1 mL), 1208C, 10 h
under N2. Numbers in parentheses indicate isomeric ratio.
AgO and CuACHTUNGTRENNUNG(OAc)2·H2O turned out to be unsuitable for ef-
ficient annulation of 8a with diphenylethyne (Table 3, en-
tries 7 and 8). Further screening of reaction conditions re-
vealed that the use of 2.0 equiv Ag2CO3 increased the yield
to 82% (Table 3, entry 9).
With the optimized conditions in hand, we examined the
À
scope of this C H annulation protocol (Scheme 7). Ethyl (1-
phenylvinyl)phosphonic monoester 8a reacted with diaryl-
substituted alkynes to give 9a and 9b in high yields. Unsym-
metrical internal alkynes and dialkyl-substituted alkynes
also worked well (9c–e).
À
Scheme 8. Competition experiments of C H annulation by using phos-
phonic monoester 3a.
Electron-deficient alkenylphosphonic monoesters under-
went efficient cyclization with alkynes, affording the desired
product 9g and 9h in 78 and 73% yields, respectively. We
were pleased to obtain annulated products 9i, 9j, and 9k
from the reaction of ethyl prop-1-en-2-ylphosphonic mono-
ester. Considering the potential bioactivities of phosphorous
2-pyrones, this approach for the syntheses of phosphorous 2-
pyrones is valuable for future applications.
À
a carboxylic acid functional group for C H functionaliza-
tion.
Next, mechanistic studies with isotopically labeled sub-
strate [D5]-3a revealed the C H bond metalation to be irre-
À
versible in nature (Scheme 9). A significant KIE was ob-
served (kH/kD =5.3),[13] implying that C H bond cleavage at
À
the 2-position of phosphonic monoester is most likely in-
volved in the rate-determining step.
Mechanistic studies: We conducted a series of experiments
Further insightful data were acquired by intermolecular
competition experiments between a range of alkynes with
ethyl phenylphosphonic monoester (3a) (Scheme 10). Sub-
strate 3a was treated with diphenylethyne and dec-5-yne
(1.5 equiv each) to produce the corresponding phosphaiso-
coumarin 5a predominantly. A competition experiment be-
tween electron-rich and electron-deficient diaryl-substituted
alkyne afforded mainly phosphaisocoumarin 5b derived
from the electron-rich alkyne. These results revealed that
electron-rich alkynes were preferentially converted into the
À
to establish the C H annulation reaction mechanism. First,
competition experiments with 3a were conducted to gain in-
sight into the innate ability of phosphonic monoester as a di-
À
recting group for C H bond activation (Scheme 8). Treat-
ment of equimolar amounts of phenylphosphonic monoester
(3a) and benzoic acid (10) with 2 equiv diphenylethyne
under the optimized reaction conditions gave 5a and 11 in
69 and 70% yields, respectively; thereby, the phosphonic
monoester turned out to be a directing group as effective as
Chem. Eur. J. 2013, 19, 16461 – 16468
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16465

P. H. Lee et al.
Conclusion
We have described a rhodium-catalyzed oxidative phosphai-
socoumarin synthesis by using cyclization of phosphonic
acid derivatives with alkynes. A range of both diarylphos-
phinic acids and arylphosphonic monoesters were selectively
cyclized in high yield with excellent functional group toler-
ance. Additionally, we found that the reaction with alkenyl-
phosphonic monoesters proceeded smoothly to afford the
corresponding phosphorus 2-pyrones through oxidative an-
À
nulations with alkynes. Mechanistic studies indicate that C
H bond metalation is irreversible and a rate-determining
key step.
Scheme 9. Experiments with isotopically labeled compound.
Experimental Section
General procedure for Rh-catalyzed
oxidative cyclization of arylphosphinic
acid 1a with dialkyl substituted al-
kynes: To
added diphenylphosphinic acid (1a;
32.7 mg, 0.15 mmol), hex-3-yne
(18.5 mg, 0.23 mmol), [{Cp*RhCl2}2]
(1.9 mg, 0.003 mmol), Ag2CO3
a screw-top V-Vial were
(41.0 mg, 0.15 mmol), and AgOAc
(26.0 mg, 0.15 mmol) in tBuOH
(1.0 mL). The resulting mixture was
stirred under air at 908C (bath temper-
ature) for 16 h. After filtration
through Celite and evaporation of the
solvents in vacuo, the crude product
Scheme 10. Alkyne competition experiments.
was purified by column chromatogra-
phy on silica gel (EtOAc/hexane=1:2)
to give 2a (42.0 mg, 93%) as a color-
less oil. Rf =0.3 (EtOAc/hexane=1:1);
desired product, which is similar to Rh-catalyzed oxidative
annulation of carboxylic acids.
In light of these experiments, a plausible mechanism for
the reaction of phosphonic monoester with alkyne was de-
veloped (Scheme 11). The proposed catalytic cycle is initiat-
ed by coordination of the phosphonic monoester to RhIII to
1H NMR (400 MHz, CDCl3): d=7.82–7.77 (m, 2H), 7.59–7.51 (m, 2H),
7.50–7.44 (m, 3H), 7.30–7.26 (m, 1H), 2.60–2.34 (m, 4H), 1.23–1.16 ppm
(m, 6H); 13C NMR (100 MHz, CDCl3): d=150.8 (d, J=11.5 Hz), 137.4
(d, J=5.3 Hz), 132.7 (d, J=2.8 Hz), 132.6 (d, J=2.3 Hz), 132.2 (d, J=
10.9 Hz), 130.6 (d, J=12.4 Hz), 130.3 (d, J=144.2 Hz), 128.4 (d, J=
13.8 Hz), 126.7 (d, J=14.5 Hz), 123.6 (d, J=129.8 Hz), 123.5 (d, J=
10.0 Hz), 114.4 (d, J=11.2 Hz), 25.5 (d, J=4.8 Hz), 20.9, 14.2, 11.6 ppm;
31P NMR (121 MHz, CDCl3): d=10.34 ppm; IR (film): 3059, 1633, 1469,
1240, 1130, 1046 cmÀ1; HRMS (EI): m/z calcd for C26H19O2P: 298.1123;
found: 298.1123.
afford rhodiumACHTUNGTRENNUNG(III) phosphonate I. Subsequent o-metalation
to furnish rhodacycle intermediate II, alkyne insertion, and
reductive elimination gives the corresponding cyclized prod-
ucts, phosphaisocoumarins or phosphorous 2-pyrones.
General procedure for Rh-catalyzed oxidative cyclization of phenylphos-
phonic monoester 3a with alkynes: To a screw-top V-Vial were added
ethyl phenylphosphonic monoester (3a; 28.0 mg, 0.15 mmol), diphenyle-
thyne (4a; 40.0 mg, 0.23 mmol), [{Cp*RhCl2}2] (1.9 mg, 0.003 mmol),
Ag2CO3 (41.0 mg, 0.15 mmol), and AgOAc (26.0 mg, 0.15 mmol) in
tBuOH (1 mL). The resulting mixture was stirred under air at 1208C
(bath temperature) for 16 h. After filtration through Celite and evapora-
tion of the solvents in vacuo, the crude product was purified by column
chromatography on silica gel (EtOAc/hexane=1:3) to give 5a (49.0 mg,
90%) as a white solid. Rf =0.3 (EtOAc/hexane=1:3); m.p. 123–1268C;
1H NMR (400 MHz, CDCl3): d=7.94–7.92 (m, 1H), 7.50–7.40 (m, 2H),
7.39–7.33 (m, 3H), 7.25–7.11 (m, 7H), 6.98–6.93 (m, 1H), 4.33–4.19 (m,
2H), 1.32 ppm (t, J=7.08 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
147.8 (d, J=10.66 Hz), 140.2 (d, J=6.95 Hz), 136.0, 134.5 (d, J=5.85),
132.8 (d, J=3.50 Hz), 131.5, 129.3 (d, J=9.11 Hz), 128.89, 128.85, 128.5,
127.8, 127.66, 127.64 (d, J=15.33 Hz), 127.1 (d, J=11.91 Hz), 120.9 (d,
J=181.70 Hz), 119.8 (d, J=12.02 Hz), 63.0 (d, J=7.21 Hz), 16.4 ppm (d,
J=5.86 Hz); 31P NMR (121 MHz, CDCl3): d=10.58 ppm; IR (film): 2982,
Scheme 11. A proposed mechanism.
16466
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 16461 – 16468

Phosphaisocoumarins and Phosphorous 2-Pyrones
FULL PAPER
1591, 1469, 1443, 1275, 1023, 953, 757 cmÀ1; HRMS (EI): m/z calcd for
raphy on silica gel (EtOAc/hexane=1:2) to give 6p (54.0 mg, 62%) as
C22H19O3P: 362.1072; found: 362.1072.
a pale-green solid. Rf =0.3 (EtOAc/hexane=1:5); m.p. 225–2288C;
1H NMR (400 MHz, CDCl3): d=8.02–8.00 (m, 1H), 7.80–7.76 (m, 1H),
7.44–7.40 (m, 6H), 7.35–7.13 (m, 14H), 4.26–4.15 (m, 2H), 1.24 ppm (t,
J=7.06 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=161.1, 151.8, 148.5 (d,
J=10.47 Hz), 139.1 (d, J=6.79 Hz), 137.3 (d, J=16.69 Hz), 135.1, 134.0
(d, J=5.37 Hz), 133.6, 132.4, 131.3, 130.2 (d, J=117.00 Hz), 129.36,
129.31, 129.26, 129.21, 128.9, 128.8, 128.6, 128.5, 128.0 (d, J=11.93 Hz),
127.8 (d, J=17.43 Hz), 126.9 (d, J=10.49 Hz), 126.7, 123.3 (d, J=
2.43 Hz), 119.9 (d, J=11.00 Hz), 116.4, 63.5 (d, J=6.66 Hz), 16.3 ppm (d,
J=5.82 Hz); 31P NMR (121 MHz, CDCl3): d=7.92 ppm; IR (film): 3058,
2981, 2245, 1736, 1595, 1468, 1281, 1071, 1025, 952, 701 cmÀ1; HRMS
(EI): m/z calcd for C37H27O5P: 582.1596; found: 582.1594.
General procedure for Rh-catalyzed oxidative cyclization of arylphos-
phonic monoester 3 with alkynes: To a screw-top V-Vial were added
ethyl o-tolylphosphonic monoester (30.0 mg, 0.15 mmol), 1,2-di-p-tolyle-
thyne (46.4 mg, 0.23 mmol), [{Cp*RhCl2}2] (1.9 mg, 0.003 mmol), Ag2CO3
(41.0 mg, 0.15 mmol), and AgOAc (26.0 mg, 0.15 mmol) in tBuOH
(1 mL). The resulting mixture was stirred under air at 908C (bath temper-
ature) for 16 h. After filtration through Celite and evaporation of the sol-
vents in vacuo, the crude product was purified by column chromatogra-
phy on silica gel (EtOAc/hexane=1:3) to give 6e (55.8 mg, 92%) as
a
pale-yellow solid. Rf =0.3 (EtOAc/hexane=1:3); m.p. 72–758C;
1H NMR (400 MHz, CDCl3): d=7.32–7.26 (m, 1H), 7.18–7.11 (m, 5H),
7.07–7.05 (m, 2H), 6.95 (d, J=8.04 Hz, 2H), 6.79–6.76 (m, 1H), 4.31–4.14
(m, 2H), 2.75 (d, J=1.04 Hz, 3H), 2.37 (s, 3H), 2.25 (s, 3H), 1.33 ppm (t,
J=7.08 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=147.1 (d, J=
10.98 Hz), 141.4 (d, J=7.33 Hz), 141,1 (d, J=9.10 Hz), 138.3, 137.4,
133.6, 132.3 (d, J=2.19 Hz), 131.7 (d, J=6.60 Hz), 131.4, 129.8, 129.6 (d,
J=5.28 Hz), 128.7, 128.3, 125.1 (d, J=12.00 Hz), 119.4 (d, J=177.17 Hz),
118.8 (d, J=11.74 Hz), 62.6 (d, J=7.20 Hz), 21.5 (d, J=4.92 Hz), 21.2 (d,
J=7.32 Hz), 16.4 ppm (d, J=6.38 Hz); 31P NMR (161 MHz, CDCl3): d=
General procedure for Rh-catalyzed oxidative cyclization of alkenylphos-
phonic monoester 8 with alkynes: To a test tube were added alkenylphos-
phonic monoester (8a; 32.0 mg, 0.15 mmol), diphenylethyne (4a;
40.0 mg, 0.23 mmol), [{Cp*RhCl2}2] (1.9 mg, 0.003 mmol), and Ag2CO3
(41.0 mg, 0.15 mmol) in DMF (0.75 mL). The resulting mixture was
stirred at 1208C (bath temperature) for 10 h under N2. After filtration
through Celite and evaporation of the solvents in vacuo, the crude prod-
uct was purified by column chromatography on silica gel (EtOAc/
hexane=1:1) to give 9a (47.0 mg, 80%) as a colorless oil. Rf =0.3
(EtOAc/hexane=1:1); 1H NMR (400 MHz, CDCl3): d=7.72–7.70 (m,
2H), 7.42–7.34 (m, 3H), 7.31–727 (m, 5H), 7.25–7.17 (m, 6H), 4.28–4.18
(m, 2H), 1.29 ppm (t, J=7.08 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
150.8 (d, J=12.76 Hz), 142.1, 142.0, 138.1 (d, J=1.18 Hz), 134.7 (d, J=
10.11 Hz), 133.2 (d, J=6.04 Hz), 129.5, 129.3, 129.1, 128.9 (d, J=
4.51 Hz), 128.5, 127.8, 127.6, 127.1 (d, J=7.30 Hz), 124.2 (d, J=
168.42 Hz), 117.7 (d, J=16.17 Hz), 63.7 (d, J=6.99 Hz), 16.3 ppm (d, J=
6.06 Hz); 31P NMR (121 MHz, CDCl3): d=9.49 ppm; IR (film): 2982,
2240, 1615, 1536, 1444, 1260, 1159, 1036, 968, 756 cmÀ1; HRMS (EI): m/z
calcd for C24H21O3P: 388.1228; found: 388.1227.
10.04 ppm; IR (film): 2981, 2238, 1609, 1508, 1260, 1027, 973, 794 cmÀ1
HRMS (EI): m/z calcd for C25H25O3P: 404.1541; found: 404.1544.
;
General procedure for Rh-catalyzed oxidative cyclization of arylphos-
phonic monoester 3 with dialkyl-substituted alkynes: To a screw-top V-
Vial were added ethyl 4-methoxyphenylphosphonic monoester (32.4 mg,
0.15 mmol), hex-3-yne (18.6 mg, 0.23 mmol), [{Cp*RhCl2}2] (1.9 mg,
0.003 mmol), Ag2CO3 (41.0 mg, 0.15 mmol), and AgOAc (26.0 mg,
0.15 mmol) in tBuOH (1 mL). The resulting mixture was stirred under air
at 908C (bath temperature) for 16 h. After filtration through Celite and
evaporation of the solvents in vacuo, the crude product was purified by
column chromatography on silica gel (EtOAc/hexane=1:1) to give 7b
À
(39.6 mg, 89%) as
a
pale-yellow oil. Rf =0.3 (EtOAc/hexane=1:1);
Competition experiments of C H annulation between phosphonic mono-
1H NMR (400 MHz, CDCl3): d=7.79 (dd, J=14.56, 8.48 Hz, 1H), 6.94–
6.90 (m, 2H), 4.20–4.05 (m, 2H), 3.87 (s, 3H), 2.57–2.42 (m, 4H), 1.30 (t,
J=7.06 Hz, 3H), 1.22 (t, J=7.38 Hz, 3H), 1.16 ppm (t, J=7.52 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=163.3 (d, J=2.99 Hz), 152.3 (d, J=
10.60 Hz), 140.9 (d, J=8.17 Hz), 131.6 (d, J=10.29 Hz), 114.5 (d, J=
11.73 Hz), 113.2 (d, J=186.63 Hz), 111.8 (d, J=16.42 Hz), 109.9 (d, J=
13.40 Hz), 62.3 (d, J=6.41 Hz), 55.3, 25.4 (d, J=5.86 Hz), 20.9, 16.3 (d,
J=6.34 Hz), 14.1, 11.7 ppm; 31P NMR (161 MHz, CDCl3): d=12.01 ppm;
IR (film): 2970, 1630, 1598, 1475, 1268, 1165, 1031, 956, 822 cmÀ1; HRMS
(EI): m/z calcd for C15H21O4P: 296.1177; found: 296.1179.
ester 3a and benzoic acid 10: To a screw-top V-Vial were added ethyl
phenylphosphonic monoester (3a; 28.0 mg, 0.15 mmol), benzoic acid (10;
18.3 mg, 0.15 mmol), diphenylethyne (4a; 53.4 mg, 0.3 mmol),
[{Cp*RhCl2}2] (1.9 mg, 0.003 mmol), Ag2CO3 (41 mg, 0.15 mmol), and
AgOAc (26 mg, 0.15 mmol) in tBuOH (1.0 mL). The resulting mixture
was stirred at 1208C (bath temperature) for 16 h under air. After filtra-
tion through Celite and evaporation of the solvents in vacuo, the crude
product was purified by column chromatography on silica gel (EtOAc/
hexane=1:3) to give 5a (37.5 mg, 69%) and 11 (31.3 mg, 70%).
Experiments with isotopically labeled substrates: To a solution of ethyl
1,2,3,4,5-pentadeuteriophenylphosphonic monoester ([D5]-3a; 38.0 mg,
0.2 mmol) in tBuOH (1.3 mL), were added diphenylethyne (4a; 53.5 mg,
0.3 mmol), [{Cp*RhCl2}2] (2.5 mg, 2 mol%), Ag2CO3 (55.0 mg,
0.2 mmol), and AgOAc (33.0 mg, 0.2 mmol). The resulting mixture was
stirred under air at 1208C (bath temperature) for 16 h. After filtration
through Celite and evaporation of the solvents in vacuo, the crude prod-
uct was purified by column chromatography on silica gel (EtOAc/
hexane=1:3) to give the desired product (60.0 mg, 82%) as a white solid.
Rf =0.3 (EtOAc/hexane=1:3); m.p. 124–1278C; 1H NMR (400 MHz,
CDCl3): d=7.98–7.92 (m, 0.08H), 7.49–7.41 (m, 0.16H), 7.35–7.34 (m,
3H), 7.25–7.11 (m, 7H), 6.98–6.94 (m, 0.08H), 4.33–4.19 (m, 2H),
1.32 ppm (t, J=7.06 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=146.7 (d,
J=10.66 Hz), 139.0 (d, J=6.93 Hz), 135.0, 133.4 (d, J=5.60), 131.7 (d,
J=2.48 Hz), 130.4, 128.2 (d, J=9.00 Hz), 127.85, 127.80, 127.4, 126.8,
126.62, 127.60 (d, J=15.39 Hz), 126.0 (d, J=12.00 Hz), 119.7 (d, J=
167.72 Hz), 118.7 (d, J=11.70 Hz), 61.9 (d, J=6.64 Hz), 15.4 ppm (d, J=
6.01 Hz); 31P NMR (121 MHz, CDCl3): d=10.64 ppm; IR (film): 2981,
2352, 1598, 1444, 1263, 1159, 1057, 1023, 944, 755 cmÀ1; HRMS (EI): m/z
calcd for C22H15D4O3P: 366.1323; found: 366.1322.
Synthesis of compound 6o: To a screw-top V-Vial were added ethyl thio-
phen-2-ylphosphonic monoester (28.8 mg, 0.15 mmol), diphenylethyne
(4a; 40.0 mg, 0.23 mmol), [{Cp*RhCl2}2] (1.9 mg, 0.003 mmol), Ag2CO3
(41.0 mg, 0.15 mmol), and AgOAc (26.0 mg, 0.15 mmol) in tBuOH
(1.0 mL). The resulting mixture was stirred under air at 908C (bath tem-
perature) for 16 h. After filtration through Celite and evaporation of the
solvents in vacuo, the crude product was purified by column chromatog-
raphy on silica gel (EtOAc/hexane=1:2) to give 6o (42.0 mg, 76%) as
a yellow oil. Rf =0.3 (EtOAc/hexane=1:2); 1H NMR (400 MHz, CDCl3):
d=7.61 (q, J=3.89 Hz, 1H), 7.36–7.32 (m, 3H), 7.26–7.12 (m, 7H), 6.73
(q, J=2.80, 1H), 4.34–4.20 (m, 2H), 1.38 ppm (t, J=7.08 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=149.7 (d, J=9.14 Hz), 148.4 (d, J=
11.90 Hz), 136.3, 133.6 (d, J=7.18 Hz), 132.8 (d, J=10.12 Hz), 130.7,
128.9, 128.6, 127.9, 127.7, 127.4, 127.2, 116.2 (d, J=8.99 Hz), 116.1 (d, J=
200.43 Hz), 63.9 (d, J=6.60 Hz), 16.4 ppm (d, J=6.09 Hz); 31P NMR
(121 MHz, CDCl3): d=5.82 ppm; IR (film): 2982, 2241, 1595, 1490, 1268,
1200, 1116, 1005, 966, 741 cmÀ1; HRMS (EI): m/z calcd for C20H17O3PS:
368.0636; found: 368.0633.
Synthesis of compound 6p: To a screw-top V-Vial were added 4-(ethoxy-
A
Intermolecular competition experiment between substrates 3a and [D5]-
(4a; 67.0 mg, 0.33 mmol), [{Cp*RhCl2}2] (1.9 mg, 0.003 mmol), Ag2CO3
(41.0 mg, 0.15 mmol), and AgOAc (26.0 mg, 0.15 mmol) in tBuOH
(1.0 mL). The resulting mixture was stirred under air at 908C (bath tem-
perature) for 16 h. After filtration through Celite and evaporation of the
solvents in vacuo, the crude product was purified by column chromatog-
3a: A mixture of ethyl phenylphosphonic monoester (3a; 18.0 mg,
0.1 mmol), ethyl 1,2,3,4,5-pentadeuteriophenylphosphonic monoester
([D5]-3a; 19.0 mg, 0.1 mmol), diphenylethyne (4a; 53.5 mg, 0.3 mmol),
[{Cp*RhCl2}2] (2.5 mg, 2 mol%), Ag2CO3 (55 mg, 0.2 mmol), and AgOAc
(33.0 mg, 0.2 mmol) in tBuOH (1.3 mL) was stirred under air at 1208C
Chem. Eur. J. 2013, 19, 16461 – 16468
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16467

P. H. Lee et al.
(bath temperature) for 1 h. After filtration through Celite and evapora-
tion of the solvents in vacuo, the crude product was purified by column
chromatography on silica gel (EtOAc/hexane=1:3) to give 5a and [D4]-
5a (8.0 mg, 11%) as a white solid. The ratio of 5a/[D4]-5a was deter-
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1
mined to be 86:14 by H NMR spectroscopic analysis.
Competition experiments with alkyne: To a screw-top V-Vial were added
ethyl phenylphosphonic monoester (3a; 28.0 mg, 0.15 mmol), diphenyle-
thyne (4a; 40.0 mg, 0.23 mmol), dec-5-yne (20.7 mg, 0.23), [{Cp*RhCl2}2]
(1.9 mg, 0.003 mmol), Ag2CO3 (41.0 mg, 0.15 mmol), and AgOAc
(26.0 mg, 0.15 mmol) in tBuOH (1.0 mL). The resulting mixture was
stirred at 908C (bath temperature) for 16 h under air. After filtration
through Celite and evaporation of the solvents in vacuo, the crude prod-
uct was purified by column chromatography on silica gel (EtOAc/
hexane=1:3) to give 5a (44.0 mg, 81%) and 5g (4.8 mg, 10%).
À
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Acknowledgements
This work was supported by a National Research Foundation of Korea
(NRF) grant funded by the Korea government (MSIP) (No. 2011–
0018355) and BRL (2009–0087013).
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Received: July 8, 2013
Published online: October 10, 2013
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