Rhodium-catalyzed oxidative cyclization of arylphosphonic acid monoethyl esters with alkenes: Efficient synthesis of benzoxaphosphole 1-oxides

Article abstract of DOI:10.1021/ol401775t

Rhodium-catalyzed tandem oxidative alkenylation and an intramolecular oxy-Michael reaction were developed using arylphosphonic acid monoethyl esters and alkenes under aerobic conditions, which produced benzoxaphosphole 1-oxides in good to excellent yields

Full text of DOI:10.1021/ol401775t

ORGANIC
LETTERS
2013
Vol. 15, No. 15
3986–3989
Rhodium-Catalyzed Oxidative Cyclization
of Arylphosphonic Acid Monoethyl Esters
with Alkenes: Efficient Synthesis of
Benzoxaphosphole 1‑Oxides
Taekyu Ryu, Jaeeun Kim, Youngchul Park, Sanghyuck Kim, and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 200-701,
Republic of Korea
phlee@kangwon.ac.kr
Received June 23, 2013
ABSTRACT
Rhodium-catalyzed tandem oxidative alkenylation and an intramolecular oxy-Michael reaction were developed using arylphosphonic acid
monoethyl esters and alkenes under aerobic conditions, which produced benzoxaphosphole 1-oxides in good to excellent yields.
CÀH bond functionalizations catalyzed by transition
metals have been demonstrated to be a very streamlined
method for the formation of CÀC and CÀheteroatom
bonds.1 In particular, ortho CÀH bond functionalizations
can be accomplished by the employment of a variety of
directing groups with the aid of coordination of transition
metals. In a number of directing groups for CÀH bond
functionalizations,2 nitrogen-containing compounds,3À5
carboxyl and hydroxyl ones6,7 have been broadly
investigated.
Recently, our attention in the CÀH bond functionaliza-
tions catalyzed by transition metals has been concentrated
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J.; Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew. Chem., Int. Ed. 2007, 46,
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r
10.1021/ol401775t
Published on Web 07/25/2013
2013 American Chemical Society

on phosphoryl-related directing groups.8 Although the
phosphonic acid and its derivatives have been used as
essential compounds in the field of organic, bioorganic,
and medicinal chemistry,9 their application in CÀH bond
functionalizations catalyzed by transition metals has been
scarcely investigated.10,11 Furthermore, the structural var-
iation of phosphonic acid derivatives would be more
flexible than that of carboxylic acid derivatives by intro-
duction of different groups to the pentavalent phosphorus
atom. In this regard, we have been interested in developing
an efficient synthetic method for a wide range of organo-
phosphorus compounds with the purpose of making fo-
cused chemical libraries effective for chemical biology
study and drug discovery.8,12
Previously, Miura reported that benzoic acid reacted
with acrylate, acrylamide, and acrylonitrile in the presence
of rhodium catalyst to afford 7-vinylphthalide along
with its dehydrogenated derivative.13 Also, Ackermann
have disclosed ruthenium-catalyzed oxidative CÀH bond
alkenylations.14 Herein, we report for the first time
rhodium-catalyzed tandem oxidative alkenylation and intra-
molecular oxy-Michael reaction using arylphosphonic
acid monoethyl esters and alkenes under aerobic condi-
tions, thus producing benzoxaphosphole 1-oxides which
have been barely studied (Scheme 1).15 Furthermore,
tandem dialkenylation and oxy-Michael reaction are
described.
Scheme 1. Rhodium-Catalyzed Oxidative Cyclization Using
Arylphosphonic Acid Monoethyl Esters
We began by screening the reaction between ortho-
tolylphosphonic acid monoethyl ester 1a and methyl acry-
late 2a in the presence of [Cp*RhCl2]2 as a catalyst and
AgOAc as an oxidant with a variety of bases and solvents
(Table 1). Reactions with a base gave a mixture of the
cyclized product 3a and alkenylated product 4a (entries
1À8). Following alkenylation of phosphonic acid, alkeny-
lated product 4a undergoes oxy-Michael reaction to give
the corresponding 3a product. Among the intensive bases
tested, Na2HPO4 was found to enhance the selectivity of
the product ratio (entry 4). However, the tandem reaction
was not completed still and thus, intermediate 4a was
produced in 28% yield. Accordingly, a number of solvents
such as t-AmOH, 1,4-dioxane, DMF, xylene, toluene, and
CH3CN were examined in the presence of Na2HPO4.
Although xylene and toluene provided 3a in good yields,
4a did not entirely disappear during the tandem reaction
(entries 12 and 13). Further screening of the solvent
revealed that the use of CH3CN as a solvent improved
the yield of 3a to 89% (85% isolated yield, dr = 1:1.1)
(entry 14). Notably, ortho-alkenylated product 4a was not
detected. When Na2HPO4 was not used (entry 15), 19% of
3a was only observed because deprotonation of the phos-
phonic acid monoethyl ester to give the corresponding salt
which triggers CÀH activation in a similar manner to that
of benzoic acid substrates did not occur effectively.16
Reactions of 1a with various electron-deficient alkenes 2
were carried out under the optimized conditions to deter-
mine the scope and limitations of the present method
(Scheme 2). The scope of the tandem ortho-alkenylation
and oxy-Michael reaction is broad, and various electron-
deficient alkenes could be successfully employed. n-Butyl
acrylate reacted with 1a to furnish 3b in 87% yield. Methyl
vinylketone and ethyl vinyl ketone workedwell too (3cand
3d). When 1a was subjected to acrylonitrile, the cyclized
product 3e was isolated in 90% yield. We were pleased to
obtainbenzoxaphosphole1-oxide 3f(71%) from 1aand N,
N-dimethyl acrylamide. Vinyl phosphate and vinyl sulfone
(3 equiv) reacted with 1a to afford 3g and 3h in 61% and
71% yields, respectively. However, styrene, 4-phenyl-1-
butene, cyclohexene, vinyltriethoxysilane, and vinyltri-
methylsilane failed to give benzoxaphosphole 1-oxide.
With these results in hand, diverse arylphosphonic acid
monoethyl esters were examined under the standard con-
ditions using methyl acrylate (Scheme 3). A substrate
(7) For the use of hydroxyl groups, see: (a) Lu, Y.; Wang, D.-H.;
Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 5916. (b) Wang, X.;
Lu, Y.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 12203. (c) Lu,
Y.; Leow, D.; Wang, X.; Engle, K. M.; Yu, J.-Q. Chem. Sci. 2011, 2, 967.
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2013, 15, 2692. (b) Chan, L. Y.; Kim, S.; Ryu, T.; Lee, P. H. Chem.
Commun. 2013, 49, 4682. (c) Seo, J.; Park, Y.; Jeon, I.; Ryu, T.; Park, S.;
Lee, P. H. Org. Lett. 2013, 15, 3358. (d) Park, S.; Seo, B.; Shin, S.; So,
J.-Y.; Lee, P. H. Chem. Commun. DOI: 10.1039/C3CC44995E.
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Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029. (c) Surry, D. S.;
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Cheong, L.; Kim, S. Org. Lett. 2013, 15, 2186. (c) Jeon, W. H.; Lee, T. S.;
Kim, E. J.; Moon, B.; Kang, J. Tetrahedron 2013, 69, 5152. (d) Unoh, Y.;
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Org. Lett., Vol. 15, No. 15, 2013
3987

Table 1. Reaction Optimizationa
Scheme 2. Rh-Catalyzed Oxidative Cyclization of 1aa
entry
base
solvent
yield (%)b,c
1
LiOAc
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-AmOH
1,4-dioxane
DMF
42 (57)
47 (50)
16(77)
2
Li2CO3
3
NaHCO3
Na2HPO4
KH2PO4
K2HPO4
K2CO3
4
63 (28)
31 (69)
55 (45)
26 (58)
25 (49)
35 (57)
39 (53)
55(17)
5
6
7
8
CsF
9
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
none
10
11
12
13
14
15
xylene
65(12)
toluene
CH3CN
CH3CN
66(13)
89 (1<, 1:1.1d)
19 (23, 56e)
a Reaction conditions: 1a (0.2 mmol), 2 (2 equiv), [Cp*RhCl2]2
(4 mol %), AgOAc (2 equiv), Na2HPO4 (1 equiv), and CH3CN (2 mL)
at 110 °C for 16 h. Isolated yields. Numbers in parentheses indicate
diastereomeric ratio. b Alkene (3 equiv) and CH3CN (1 mL) were used.
a Reaction conditions: 1a (0.2 mmol), 2a (2 equiv), [Cp*RhCl2]2
(4 mol %), AgOAc (2 equiv) in solvent (2 mL) at 110 °C for 16 h. b 1
H
NMR yields of 3a using CH2Br2 as an internal standard. c Numbers in
parentheses are 1H NMR yield of 4a. d Diastereomeric ratio. e Yield
of 1a.
Scheme 3. Rh-Catalyzed Oxidative Cyclizationa
having a 2-ethyl and 2-methoxy group on the phenyl ring
promoted alkenylation followed by oxy-Michael reac-
tion, thus producing the benzoxaphosphole 1-oxides 3i
and 3j in 89% and 85% yields, respectively. Reaction with
2-phenylated phosphonic acid monoethyl ester 1k also pro-
duced the cyclized product 3k in quantitative yield (98%).
Substrate 1l possessing an electron-withdrawing chloro
group was all smoothly cyclized to provide 3l in 80% yield.
The tolerance of the chloro group is particularly impor-
tant, as the following catalytic cross-couplings are hopeful.
When substrate 1m bearing a 2,3-dimethyl group was
subjected to the standard conditions, the desired tandem
product 3m was isolated in 90% yield. However, 2,5-
dimethyl substituted substrate 1n was less reactive due to
the steric effect and the cyclized product 3n was isolated in
35% yield along with the starting material (65%). Aryl-
phosphonic acid monoethyl ester 1o having both a
2-methyl and 4-methoxy group was cyclized to 3o in
86% yield. Substrate 1p bearing a 1-naphthalenyl group
worked well too, resulting in the formation of 3p in
82% yield.
b
a Numbers in parentheses indicate diastereomeric ratio. Recovery
yield of starting material.
commonly used in organic synthesis were tolerated. When
electron-withdrawing 4-fluoro and 4-acetyl substituted
phosphonic acids were used, the corresponding cyclized
products 5d and 5e were obtained in good yields. The
tolerance of the fluoroand ketonegroupon thephenyl ring
is especially useful, providing an opportunity for further
functionalization. A substrate bearing a 4-bromo group
was smoothly cyclized to provide 5f in 59% yield. However,
when substrates having a 3-bromo and 3-methyl group
were subjected to the Rh-catalyst, ortho-alkenylation
Next, when phenylphosphonic acid monoethyl ester was
treated with methyl acrylate under the standard condi-
tions, 7-alkenylated benzoxaphosphole 1-oxide 5a was
obtained selectively in 76% yield through tandem dialke-
nylation and an oxy-Michael reaction (Scheme 4). Surpris-
ingly, 7-alkenylated benzoxaphosphole 1-oxide having an
exo-methylene group at the 3-position was not contam-
inated.13 Subjecting substrates having a methyl and meth-
oxy group at the para-position to 2a furnished 5b and 5c
in 75% and 77% yields, respectively. Functional groups
3988
Org. Lett., Vol. 15, No. 15, 2013

only occurred and then, 2-alkenylated products 4b and 4c
were obtained in 50% and 68% yields, respectively. It
seems that a subtle balance between the steric and electron-
ic properties of the substituent on the phenyl ring is needed
for the tandem reaction.
As shown in Scheme 5, a plausible reaction mechanism
for the reaction of arylphosphonic acid monoethyl esters 1
with alkenes 2 is described. A proposed catalytic cycle was
initiated by coordination of 1 to Cp*RhX2(III) to provide
a rhodium(III) phosphonate I. Sequential ortho-rhodation
to provide a rhodacycle intermediate II, alkene inser-
tion, and β-hydride elimination took place to give ortho-
alkenylated arylphosphonic acid monoethyl esters 4, and
then, an oxy-Michael reaction gave rise to benzoxaphosphole
1-oxides 3.
Scheme 4. Rh-Catalyzed Cyclizationa
Scheme 5. A Plausible Mechanism
In summary, we have developed an efficient rhodium-
catalyzed tandem oxidative alkenylation and intramolecu-
lar oxy-Michael reaction from arylphosphonic acid mono-
ethyl esters and alkenes under aerobic conditions, which
produced benzoxaphosphole 1-oxides in good to excellent
yields. Moreover, arylphosphonic acid monoethyl esters
having a substituent at the para-position underwent tan-
dem dialkenylation and an oxy-Michael reaction to afford
7-alkenylated benzoxaphosphole 1-oxides. Current efforts
are directed toward the development of an efficient
reaction using a phosphoryl functional group and its
application.
a Numbers in parentheses indicate diastereomeric ratio.
To obtain insight into the reaction mechanism, a cata-
lytic CÀH bond transformation in the presence of D2O
was carried out, thus providing a significant D/H exchange
in the ortho-position of the recovered starting material
1a-[D1] (eq 1). We also performed kinetic
Acknowledgment. This work was supported by the
National Research Foundation of Korea (NRF) grant funded
by the Korea government (MSIP) (No. 2011-0018355) and
BRL (2009-0087013). P.H. thanks Prof. E. J. Yoo (KNU)
for helpful discussions and manuscript preparation. This
paper is dedicated to Professor Chul-Ho Jun, Yonsei
University, on the occasion of his 60th birthday.
isotope effect (KIE) studies (eq 2). A remarkable kinetic
isotope effect (KIE) was observed (kH/kD = 2.6),17
indicating that the CÀH bond cleavage at the ortho-
position of phosphonic acid monoethyl ester is most
likely involved in the rate-determining step.
Supporting Information Available. Experimental pro-
1
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.
(17) (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. 15, 2013
3989