Synthesis of phosphaisocoumarins through rhodium-catalyzed cyclization using alkynes and arylphosphonic acid monoesters

Article abstract of DOI:10.1021/ol401407v

A rhodium-catalyzed cyclization using alkynes and arylphosphonic acid monoesters for the synthesis of phosphaisocoumarins is reported. A number of arylphosphonic acid monoesters were selectively cyclized in high yields with functional group tolerance. In addition, unsymmetrical alkynes are applied in high regioselectivity.

Full text of DOI:10.1021/ol401407v

ORGANIC
LETTERS
2013
Vol. 15, No. 13
3358–3361
Synthesis of Phosphaisocoumarins
through Rhodium-Catalyzed Cyclization
Using Alkynes and Arylphosphonic Acid
Monoesters
Jungmin Seo, Youngchul Park, Incheol Jeon, Taekyu Ryu, Sangjune Park, and
Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 200-701,
Republic of Korea
phlee@kangwon.ac.kr
Received May 18, 2013
ABSTRACT
A rhodium-catalyzed cyclization using alkynes and arylphosphonic acid monoesters for the synthesis of phosphaisocoumarins is reported.
A number of arylphosphonic acid monoesters were selectively cyclized in high yields with functional group tolerance. In addition, unsymmetrical
alkynes are applied in high regioselectivity.
CÀH bond functionalizations catalyzed by transition
metals are interesting since these procedures permit for a
more clear-cut synthetic strategy to products devoid of
demanding prefunctionalization of starting materials, thus
avoiding byproducts in step-economical manner.1 In order
to have a broad synthetic strategy in a CÀH functionaliza-
tion, the desired CÀH bond in the starting material should
be selectively activated over all the CÀH bonds existing in
the substrate. In particular, since there is a trivial difference
in the reactivity between the CÀH bonds in aromatic
compounds, a selective CÀH bond functionalization is
very crucial. Recently, a series of examples of CÀC and
CÀheteroatom bond formation have been described by
introducingdirecting groups.2 Asaconsequcnce, anumber
of coordinating directing groups have been employed for
atom- and step-economical CÀH bond functionalization.
Among those, imines,3 amides4 and heterocyclic com-
pounds bearing nitrogen5 are most frequently utilized
as directing groups. In addition, CÀH functionalization
using hydroxyl6 and carboxyl7 as directing groups through
(3) (a) Kuninobu, T.; Tokunage, T.; Kawata, A.; Takai, K. J. Am.
Chem. Soc. 2006, 128, 202. (b) Fukutani, T.; Umeda, N.; Hirano, K.;
Satoh, T.; Miura, M. Chem. Commun. 2009, 5141.
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Int. Ed. 2011, 50, 6379. (b) Hyster, T. L.; Rovis, T. J. Am. Chem. Soc.
2010, 132, 10565. (c) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries,
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J. Am. Chem. Soc. 2002, 124, 1586. (d) Tobisu, M.; Ano, Y.; Chatani, N.
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Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254. (c) Hull,
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2009, 131, 6898. (e) Shiota, H.; Ano, Y.; Aihara, Y.; Fukumoto, Y.;
Chatani, N. J. Am. Chem. Soc. 2011, 133, 14952. (f) Aihara, Y.; Chatani,
N. J. Am. Chem. Soc. 2013, 135, 5308. (g) Kwak, J.; Ohk, Y.; Jung, Y.;
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(1) (a) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (b)
Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677. (c) Giri, R.;
Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38,
3242.
(2) (a) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936.
(b) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (c) Colby,
D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012,
45, 814. (d) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem.
Res. 2012, 45, 788. (e) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem.
€
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Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (g) Lyons, T. W.; Sanford,
M. S. Chem. Rev. 2010, 110, 1147. (h) Ackermann, L.; Vicente, R.;
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r
10.1021/ol401407v
Published on Web 06/21/2013
2013 American Chemical Society

weak coordination has been studied to a great extent.1,2
However, there is still a need to develop useful functional
groups for direct ortho-selective CÀH bond cleavage,
which will provide a significant effect in synthetic applica-
tions. Encouraged by a number of transition metal-
catalyzed cyclizations using a carboxylic acid group,8 we
imagined that CÀH bond functionalization with phos-
phonic acid monoesters would perform as an desirable
platform for the preparation of phosphaisocoumarins,
which may be phosphorus heterocycles exhibiting effective
biological activity.9
Scheme 1. Rh-Catalyzed Cyclization Using Alkynes and
Phosphonic Acid Monoester
Moreover, to date, phosphaisocoumarin scaffolds have
been synthesized through intramolecular cyclization.
Although alkynylarylphosphates9k or their monoesters9g,h
have been used in the cyclization (eqs 1 and 2), as far as we
know, a rhodium-catalyzed cyclization using alkynes and
arylphosphonic acid monoesters has not been utilized for
the synthesis of phosphaisocoumarins.
Table 1. Reaction Optimizationa
temp time yieldb
entry
oxidant (equiv)
solvent
(°C)
(h)
(%)
1
2
3
4
5
6
7
8
9
Cu(OAc)2 H2O (0.1)
DMF
DMF
120
120
18
18
18
18
18
18
18
18
16
16
16
16
16
16
16
0
0
3
Ag2CO3 (0.5)
Ag2CO3 (0.5)
Ag2CO3 (0.5)
Ag2CO3 (0.5)
Ag2CO3 (0.5)
Ag2CO3 (0.5)
Ag2CO3 (0.5)
Ag2CO3 (0.5)
1,4-dioxane 110
xylene 120
30
10
15
0
mesitylene 170
CF3CH2OH 90
C6F5OH
t-AmOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
150
110
90
0
55
57
0
Furthermore, to the best of our knowledge, methods
using phosphorus compound as a directing group is few.10
Inspired by recent our interests11 in organophosphorus
compounds, we decided to examine CÀH bond functio-
nalization with phosphonic acid monoester. Herein, we
have described Rh-catalyzed cyclization using alkynes and
phosphonic acid monoester for the synthesis of phosphai-
socoumarins (Scheme 1).
10 AgSbF6 (0.5)
90
11 AgOTf (0.5)
12 AgOAc (0.5)
13 Ag2O (0.5)
90
0
90
45
0
90
14 Cu(OAc)2 H2O (0.5)
90
23
49
3
15 Ag2CO3 (0.5)/Cu(OAc)2
90
H2O (0.5)
3
16 Ag2CO3 (0.5)/AgOAc (0.5) t-BuOH
90
90
16
16
81
90
We started our studies with phenylphosphonic acid
monoester 1a (Table 1), which can be easily prepared from
17 Ag2CO3 (1)/AgOAc (1)
t-BuOH
a Reaction conditions: 1a (0.15 mmol), 2a (0.23 mmol), [Cp*RhCl2]2
(2 mol %), solvent (1 mL). b Isolated yields.
(7) (a) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010,
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14, 930. (c) Chinnagolla, R. K.; Jeganmohan, M. Chem. Commun. 2012,
48, 2030.
hydrolysis of diethyl phenylphosphonate. Miura reported
that the oxidative coupling of benzoic acids with internal
alkynes effectively proceeds in the presence of [Cp*RhCl2]2
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Mathey, F.; Nixon, J. F. Phosphorus: The Carbon Copy; John Wiley &
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and Cu(OAc)2 H2O as catalyst and oxidant, respectively,
to produce the corresponding isocoumarin derivatives.8a
3
However, when [Cp*RhCl2]2 (2 mol %) and Cu(OAc)2
3
H2O (0.1 equiv) in DMF at 120 °C for 18 h under air8a
were applied to cyclization of phenylphosphonic acid
monoester, the reaction did not proceed unfortunately
(entry 1). Also, Ag2CO3 (0.5 equiv) as an oxidant was
not effective in DMF (entry 2). Although trifluoroethanol
and pentafluorophenol were not successful solvents
(entries 6 and 7) with Ag2CO3 (0.5 equiv), 1,4-dioxane,
xylene, and mesitylene gave the desired phosphaisocou-
marin 3a in 10À30% yields (entries 3À5). tert-Butyl alco-
hol was found to be the solvent of choice (entry 9). Next,
a number of oxidants were tested and thus, the reaction
was relatively sensitive to the choice of oxidants, with
which AgSbF6, AgOTf and Ag2O were entirely ineffective
(11) (a) Mo, J.; Kang, D.; Eom, D.; Kim, S. H.; Lee, P. H. Org. Lett.
2013, 15, 26. (b) Chan, L. Y.; Kim, S.; Ryu, T.; Lee, P. H. Chem.
Commun. 2013, 49, 4682. (c) Chary, B. C.; Kim, S.; Park, Y.; Kim, J.;
Lee, P. H. Org. Lett. 2013, 15, 2692.
Org. Lett., Vol. 15, No. 13, 2013
3359

(entries 10, 11, and 13). However, AgOAc (0.5 equiv) and
Ag2CO3/Cu(OAc)2 H2O (0.5 equiv each) gave moderate
produced in 51% yield in major along with 3-methyl-4-
propylphosphaisocoumarin (32%). However, terminal
acetylenes, such as phenylacetylene, 4-phenyl-1-butyne,
propargyl bromide, and 3-butyn-1-ol, were not cyclized
with 1a.
3
transformation of the starting 1a (entries 12 and 15).
Gratifyingly, Ag2CO3/AgOAc (1 equiv each) turned out
to be the most effective oxidant, resulting in the complete
use of 1a to furnish 3a in 90% yield in DMF at 120 °C for
16 h (entry 17). No amount of 3a were produced in the case
using [RuCl2(p-cymene)]2 and (PCy3)2HRu(CO)Cl (see
the Supporting Information). Treatment of equimolar
mixture of 1a and benzoic acid with standard conditions
gave 3a (69%) and isocoumarin (70%). As anticipated,
this mixture was subjected to Miura conditions to afford
only isocoumarin in 89% yield.
To determine the scope and limitations of the present
method, various alkynes were applied to the standard condi-
tions (Scheme 2). With respect to the alkyne substituent,
the cyclization shows broad substrate tolerance among
internal alkynes. Reaction of 1a with various symmetrical
diarylacetylenes 2 proceeded smoothly, as that with diphe-
nylacetylene, to provide 3,4-diarylphosphaisocoumarins 3b,
3c, 3d, and 3e in good to excellent yields. However, electron-
deficient bis(3-chlorophenyl)acetylene required longer reac-
tion time (30 h) for completion of cyclization. Unsymme-
trical diarylacetylene gave the desired phosphaisocoumarin
3f in 92% yield. Electron-rich diarylacetylene is more
reactive than electron-deficient one. When unsymmetrical
alkylarylacetylenes are used, the phosphaisocoumarin hav-
ing the phenyl group proximal to the oxygen was selectively
produced due to the extended conjugation. 4-Alkyl-3-
phenylphosphaisocoumarins 3g and 3h were predominantly
obtained in 91% and 80% yields, respectively, together with
minor amounts of their regioisomers. The rhodium catalysts
were also found to be effective to dialkylalkynes, in which
3-hexyne and 5-decyne were subjected to 1a to afford 3i
and 3j in 88% and 87% yields, respectively. In the case of
2-hexyne, 4-methyl-3-propylphosphaisocoumarin 3k was
Next, the scope of the arylphosphonic acid monoesters 1
and alkynes 2 was investigated (Scheme 3). Electron-
deficient phosphonic acid monoester 1b having fluoro
group on the phenyl ring underwent efficiently cyclization
with a variety of alkynes, affording the desired phosphai-
socoumarins 3l, 3m and 3n in excellent yields. Functional
groups commonly used in organic synthesis were tolerated.
For example, substrates possessing iodo (1c) and ketone
(1d) group were all smoothly cyclized to afford 3o-3r in
high yields. The tolerance of iodo group is especially
important, as following catalytic cross-couplings are
promising. In addition, electron-rich phosphonic acid
monoester 1e, 1f and 1g having o-methyl, m-methyl and
p-methoxy on phenyl ring work equally well with
Scheme 3. Arylphosphonic Acid Monoester and Alkyne Scopea
Scheme 2. Alkyne Scopea
a Reaction conditions: 1 (0.15 mmol), 2 (0.23 mmol), [Cp*RhCl2]2
(2 mol %), Ag2CO3 (0.15 mmol), AgOAc (0.15 mmol), t-BuOH (1 mL)
at 90 °C. b Numbers in parentheses indicate isomeric ratio.
a Reaction conditions: 1 (0.15 mmol), 2 (0.23 mmol), [Cp*RhCl2]2
(2 mol %), Ag2CO3 (0.15 mmol), AgOAc (0.15 mmol), t-BuOH (1 mL)
at 90 °C. b Numbers in parentheses indicate isomeric ratio.
3360
Org. Lett., Vol. 15, No. 13, 2013

Scheme 4. Competition Experiments between Alkynes
Scheme 5. Studies with Isotopically Labeled Compounds
symmetrical and unsymmetrical diarylacetylenes as well as
dialkylacetylenes. As anticipated, m-methyl substrates un-
derwent Rh-catalyzed cyclization with alkynes regioselec-
tively at the sterically less hindered position to afford
phosphaisocoumarins 3v, 3w, and 3x having methyl group
on 7-position in high yields. In contrast, in the case of
3,4-(methylenedioxy)phenylphosphonic acid monoester
1h, CÀH bond activation occurred at C2 instead of C6
to give rise to 3ab in 90% yield because coordination of
both the 3-oxy and the phosphonic acid monoester group
probably brings about functionalization at the C2 site.
An unprotected hydroxyl group 1i was compatible with
the present conditions. Exposure of 1-naphthalenylpho-
sphonic acid monoester 1j with alkynes in the presence of
[Cp*RhCl2]2 catalyst led to the formation of phosphaiso-
coumarins 3ae, 3af, and 3ag in high yields. Substrates
containing heterocyclic moieties, such as indol and thio-
phene, underwent the cyclization, providing 3ah and 3ai
in good yield.
Competition experiments between alkynes were explored
(Scheme 4). Phenylphosphonic acid monoester 1a was
treated with diphenylacetylene and 5-decyne (1.5 equiv
each) to produce phosphaisocoumarin 3a in major
(Scheme 4, eq 3). A competition experiment between
electron-rich (p-methoxy) and electron-deficient (p-bromo)
diarylacetylenesaffordsmainlythephosphaisocoumarin3e
obtained from the electron-rich alkyne (Scheme 4, eq 4).
To obtain insight into the reaction mechanism, we carried
out kinetic isotope effect (KIE) studies (Scheme 5).
A significant KIE was detected (kH/kD = 5.3),12 indicating
that the CÀH bond cleavage at the C2 site of 1a is most
likely involved in the rate-limiting step.
Scheme 6. Plausible Mechanism
of 1 to Cp*RhX2(III) to provide a rhodium(III) phos-
phonate 4. Successive o-rhodation to afford a rhodacycle
intermediate 5, alkyne insertion and reductive elimination
took place to give phosphaisocoumarins 3.
In summary, we have developed an efficient rhodium-
catalyzed cyclization using alkynes and arylphosphonic
acidmonoesters for the synthesisof phosphaisocoumarins.
A range of substrates were selectively cyclized in high yield
with functional group tolerance. Additionally, unsymme-
trical alkynes are applied in high efficiency and regioselec-
tivity. Further studies to examine differences or similarities
between the reaction of aromatic acids and phosphonic
acids and expand the synthetic scope of this reaction are
currently underway.
Acknowledgment. This work was supported by the Na-
tional Research Foundation of Korea (NRF) grant funded
by the Korea government (MSIP) (No. 2011-0018355).
Supporting Information Available. Experimental pro-
1
A plausible mechanism for the reaction of phosphonic
acid monoesters 1 with alkynes 2 is illustrated in Scheme 6.
A proposed catalytic cycle was started by coordination
cedures, characterization data, and H and 13C NMR
spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) (a) Jones, W. D. Acc. Chem. Res. 2003, 36, 140. (b) Kakiuchi, F.;
Matsuura, Y.; Kan, S.; Chatani, N. J. Am. Chem. Soc. 2005, 127, 5936.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 13, 2013
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