Phosphoryl-related directing groups in rhodium(III) catalysis: A general strategy to diverse P-containing frameworks

Article abstract of DOI:10.1021/ol402053n

Herein, a rhodium(III)-catalyzed oxidative C-H activation of simple arylphosphonates and phosphonamides with subsequent coupling with alkenes (olefination), internal alkynes (hydroarylation and oxidative cyclization), or simple arenes to give access to diverse P-containing functional frameworks is reported.

Full text of DOI:10.1021/ol402053n

ORGANIC
LETTERS
2013
Vol. 15, No. 17
4504–4507
Phosphoryl-Related Directing Groups in
Rhodium(III) Catalysis: A General Strategy
to Diverse P‑Containing Frameworks
Dongbing Zhao,† Corinna Nimphius,† Matthew Lindale, and Frank Glorius*
€
€
€
Westfalische Wilhelms-Universitat Munster, Organisch-Chemisches Institut,
Corrensstrasse 40, 48149 Mu€nster, Germany
glorius@uni-muenster.de
Received July 21, 2013
ABSTRACT
Herein, a rhodium(III)-catalyzed oxidative CÀH activation of simple arylphosphonates and phosphonamides with subsequent coupling with
alkenes (olefination), internal alkynes (hydroarylation and oxidative cyclization), or simple arenes to give access to diverse P-containing
functional frameworks is reported.
Functionalized organophosphorus compounds are an
important class of molecules due to their ubiquity in
biological systems and their potential application in me-
dicinal chemistry, materials chemistry, and catalysis.1 How-
ever, accessible and efficient synthetic methods to modify
these privileged organophosphorus structures are surpris-
ingly underrepresented. Traditional strategies for the mod-
ification of organophosphorus compounds usually suffer
from a limited substrate scope as well as nontrivial multi-
step reaction sequences.2 Therefore, methods for the direct
functionalizations of phosphonates and phosphonamides
are desirable. This would give rise to the late stage function-
alization of natural products and biologically active com-
pounds. In recent years CÀH bond activation has become
a common technique to activate and functionalize aro-
matic CÀH bonds ortho to coordinating functional
(directing) groups. For this reason Cp*Rh(III)-catalyzed
Csp2 CÀH activation with subsequent cross-coupling with
alkenes (olefination), alkynes (hydroarylation and oxida-
tive cyclization),4,5 and/or simple arenes (CÀH/CÀH de-
hydrogenative coupling) is a rapidly evolving research
field.3 A wide range of carbonyl-derived directing groups
have been used for this transformation.4À6 Because there is
a remarkable similarity in reactivity between these carbon
species and their phosphorus counterparts, we anticipated
that the phosphonate and phosphonamide analogues
would have similar potential as directing groups
(Scheme 1). It is also important to note that a variety of
aryl phosphonate esters are commercially available or are
† These authors contributed equally.
(1) (a) Dousson, C.; Surleraux, D.; Paparin, J.; Pierra, C.; Griffon,
J.-F.; Leroy, F.; Dukhan, D. WO 2010101967 A2. (b) Hiney, R. M.;
€
Higham, L. J.; Muller-Bunz, H. D.; Gilheany, G. Angew. Chem., Int. Ed.
2006, 45, 7248. (c) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed.
2008, 47, 6338. (d) Luo, X.; Zhang, H.; Duan, H.; Liu, Q.; Zhu, L.;
ꢀ
Zhang, T.; Lei, A. Org. Lett. 2007, 9, 4571. (e) Ruiz-Gomez, G.;
ꢁ
Francesch, A.; Iglesias, M. J.; Lopez-Ortiz, F.; Cuevas, C.; Serrano-
Ruiz, M. Org. Lett. 2008, 10, 3981. (f) Laughlin, F. L.; Rheingold, A. L.;
Deligonul, N.; Laughlin, B. J.; Smith, R. C.; Higham, L. J.; Protasiewicz,
J. D. Dalton Trans. 2012, 41, 12016. (g) Kamer, P. C. J.; van Leeuwen, P.
W. N. M. Phosphorus(III) Ligands in Homogeneous Catalysis: Design
and Synthesis; Wiley-VCH: New York, 2012. (h) Corbridge, D. E. C.
Phosphorus: Chemistry, Biochemistry and Technology, 6th ed.; CRC
Press: Taylor & Francis Group, 2013.
(2) (a) Kolodiazhnyi, O. I. Russ. Chem. Rev. 2011, 80, 883. (b) Allen,
D. W.; Loakes, D.; Tebby, J. C. Organophosphorus Chemistry; RSC
Publishing: 2009. (c) Engel, R. Handbook of Organophosphorus Chemis-
try; CRC Press: 1992. (d) Quin, L. D. A Guide to Organophosphorus
Chemistry; Wiley-VCH: New York, 2000. (e) Majoral, J.-P. New Aspects in
Phosphorus Chemistry V; Springer: 2004.
(3) For recent reviews on Rh(III)-catalyzed CÀH activation, see: (a)
Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,
1013. (b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624. (c) Bouffard, J.; Itami, K. Top. Curr. Chem. 2010, 292, 231. (d)
Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212. (e) Colby, D. A.;
Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814.
(f) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (g)
Patureau, F. W.; Wencel-Delord, J.; Glorius, F. Aldrichimica Acta 2012,
45, 31.
r
10.1021/ol402053n
Published on Web 08/23/2013
2013 American Chemical Society

readily prepared by known procedures. While Kim and co-
workers recently reported the use of benzyl- and phenoxy-
phosphonic acids as competent directing groups for
palladium(II) and during the preparation of this manu-
script, Lee and Miura reported the Rh(III)-catalyzed
oxidative cyclization of alkynes and arylphosphonic acid;
however, simple arylphosphonates and phosphonamides
as directing groups in Rh(III) catalysis are still unknown
and also until now no example exists for Rh(III)-catalyzed
phosphoryl-related group directed hydroarylation and
CÀH/CÀH coupling reaction.7,8 Herein, we report a
rhodium(III)-catalyzed oxidative CÀH activation of sim-
ple arylphosphonate esters and phosphonamides and sub-
sequent coupling with alkenes (Heck reaction), internal
alkynes (hydroarylation and oxidative cyclization), or
simple arenes (dehydrogenative coupling) to give access
todiverse P-containing functional frameworks (Scheme 1).
Our preliminary investigation focused on the oxidative
Heck-type coupling of diethyl phenylphosphonate (1a)
with n-butyl acrylate. After screening several parameters
(Table S1 in the Supporting Information), the product 3a
was obtained in 77% isolated yield in the presence of the
pregenerated cationic rhodium species RhCp*(CH3CN)3-
(SbF6)2 (2.5 mol %), and Cu(OAc)2 (1.0 equiv) in DCE
under air at 130 °C for 24 h (Table S1, entry 14). Subse-
quently, we examined the scope of olefins as well as
aryl phosphonates and phosphonamides in the oxida-
tive Heck-type reaction. Overall, we were pleased with
the generality of this method. As shown in Scheme 2,
Scheme 2. Scope of the Oxidative Heck Reaction with Diverse
Aryl Phosphonates and Olefins
Scheme 1. Arylphosphonates and Phosphonamides As
Directing Groups in Rh(III) Catalysis
(4) For selected examples of the carbonyl-derived directing groups in
the Rh(III)-catalyzed oxidative Heck reaction, see: (a) Ueura, K.; Satoh,
T.; Miura, M. Org. Lett. 2007, 9, 1407. (b) Mochida, S.; Hirano, K.;
Satoh, T.; Miura, M. J. Org. Chem. 2011, 76, 3024. (c) Park, S. H.; Kim,
J. Y.; Chang, S. Org. Lett. 2011, 13, 2372. (d) Wang, F.; Song, G.; Li, X.
Org. Lett. 2010, 12, 5430. (e) Patureau, F. W.; Glorius, F. J. Am. Chem.
Soc. 2010, 132, 9982. (f) Patureau, F. W.; Besset, T.; Glorius, F. Angew.
Chem., Int. Ed. 2011, 50, 1064. (g) Rakshit, S.; Grohmann, C.; Besset, T.;
Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350. (h) Besset, T.; Kuhl, N.;
Patureau, F. W.; Glorius, F. Chem.;Eur. J. 2011, 17, 7167. (i) Will-
wacher, J.; Rakshit, S.; Glorius, F. Org. Biomol. Chem. 2011, 9, 4736. (j)
Gong, T.-J.; Xiao, B.; Liu, Z.-J.; Wan, J.; Xu, J.; Luo, D.-F.; Fu, Y.; Liu,
L. Org. Lett. 2011, 13, 3235. (k) Zhao, P.; Niu, R.; Wang, F.; Han, K.; Li,
X. Org. Lett. 2012, 14, 4166.
(5) For selected examples of carbonyl-derived directing groups in the
Rh(III)-catalyzed reaction with alkynes (hydroarylation and oxidative
cyclization), see: (a) Stuart, D. R.; Bertrand-Laperle, M.; Burgess,
K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474. (b) Schipper,
D. J.; Hutchinson, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6910.
(c) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565. (d)
Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132,
9585. (e) Huestis, M.; Chan, P. L.; Stuart, D. R.; Fagnou, K. Angew.
Chem., Int. Ed. 2011, 50, 1338. (f) Guimond, N.; Gorelsky, S. I.; Fagnou,
K. J. Am. Chem. Soc. 2011, 133, 6449. (g) Patureau, F. W.; Besset, T.;
Kuhl, N.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2154. (h) Muralirajan,
K.; Parthasarathy, K.; Cheng, C.-H. Angew. Chem., Int. Ed. 2011, 50,
4169. (i) Li, B.; Ma, J.; Liang, Y.; Wang, N.; Xu, S.; Song, H.; Wang, B.
Eur. J. Org. Chem. 2013, 1950. (j) Pham, M. V.; Ye, B.; Cramer, N.
Angew. Chem., Int. Ed. 2012, 51, 10610.
regardless of the electronic and steric effects, the phospho-
nates and phosphonamides were coupled smoothly with
olefins to afford the desired 2-(1-alkenyl)phenylphos-
phonates and 2-(1-alkenyl)phenyl phosphonamides in
satisfactory yields (Scheme 2, 3aÀi). The position of an
additional substituent on substrates had little effect on the
reaction efficiency as shown in the cases of diethyl phenyl-
phosphonates bearing a methyl or methoxy substituent at
the 2-, 3-, or 4-position (3b, 3c, 3e, and 3f, respectively). As
expected the reactions occurred preferentially at the more
sterically accessible position when a meta-substituent is
present in the phenyl ring of the aryl phosphonates
(Scheme 2, 3c). This method was remarkably compatible
with a variety of important functional groups such as
fluorine, and methoxy groups, which could be subjected
(7) (a) Meng, X.; Kim, S. Org. Lett. 2013, 15, 1910. (b) Chan, L. Y.;
Cheong, L.; Kim, S. Org. Lett. 2013, 15, 2186. (c) Chary, B. C.; Kim, S.;
Park, Y.; Kim, J.; Lee, P. H. Org. Lett. 2013, 15, 2692. (d) Chan, L. Y.;
Kim, S.; Ryu, T.; Lee, P. H. Chem. Commun. 2013, 49, 4682.
(8) (a) Seo, J.; Park, Y.; Jeon, I.; Ryu, T.; Park, S.; Lee, P. H. Org.
Lett. 2013, 15, 3358. (b) Unoh, Y.; Hashimoto, Y.; Takeda, D.; Hirano,
K.; Satoh, T.; Miura, M. Org. Lett. 2013, 15, 3258. (c) Itoh, M.;
Hashimoto, Y.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2013,
DOI:10.1021/jo401393b.
(6) Until now, only a few examples of carbonyl-derived directing
groups in Rh(III)-catalyzed dehydrogenative cross-coupling, see: (a)
Wencel-Delord, J.; Nimphius, C.; Patureau, F. W.; Glorius, F. Angew.
Chem., Int. Ed. 2012, 51, 2247. (b) Morimoto, K.; Ioh, M.; Hirano, K.;
Satoh, T.; Shibata, Y.; Tanaka, K.; Miura, M. Angew. Chem., Int. Ed.
2012, 51, 5359. (c) Wencel-Delord, J.; Nimphius, C.; Wang, H.; Glorius,
F. Angew. Chem., Int. Ed. 2012, 51, 13001.
Org. Lett., Vol. 15, No. 17, 2013
4505

to further synthetic transformations (Scheme 2, 3dÀf). We
ran two competition experiments to compare the directing
group ability of the PdO ester with a carboxylic acid ester
and an amide. For ethyl benzoate, we obtained a mixture
of 2-(1-alkenyl)phenylphosphonate and 2-(1-alkenyl)-
phenylbenzoate (approximately 1:1). For acetanilide, we
only detected the product of 2-(1-alkenyl) acetanilide but
no 2-(1-alkenyl)phenylphosphonate.
Scheme 4. Scope of the Rh(III)-Catalyzed Oxidative Cyclization
of Aryl Phosphonates and Phosphonamides
Scheme 3. Scope of the Rh(III)-Catalyzed Hydroarylation of
Aryl Phosphonates and Phosphonamides
alkynes to construct six-membered phosphaisoquinolin-1-
one derivatives. After optimization, we found that, by
treating phenylphosphonamide (1a) with diphenylacety-
lene, the oxidative cyclization product (5a) could be ob-
tained in 71% yield. The scope of the reaction is outlined in
Scheme 4. With respect to the scope of alkynes 3, we found
thatthe oftenreluctant diaryl alkynesworkwell(Scheme4,
5aÀd) and that unsymmetrical alkynes display good re-
gioselectivities (Scheme 4, 5e). Unfortunately, our catalytic
system does not tolerate terminal alkynes.
Furthermore, the preliminary result shows that the dehy-
drogenative cross-coupling of the aryl phosphonamide and
simple arenes could also be achieved in moderate yield. When
phosphonamide 1i was treated with 40 equiv of 3-chlorobro-
mobenzene as solvent under the previously reported reaction
conditions,6a biaryl 6 was formed in 41% yield (Scheme 5).
This cross-coupling represents a 2-fold CÀH activation and
allows rapid access to biaryl phosphorus derivates.
Having optimized the reaction of olefins with phospho-
nates and phosphonamides, we began studying the alkyne
hydroarylation, an important method for the synthesis of
highly substituted alkene derivatives. After optimization
we found that [RhCp*Cl2]2 with AgSbF6 in combination
with 10 mol % Cu(OAc)2 and 1.0 equiv PivOH as an
additive at 110 °C exhibited moderate catalytic activity in
the hydroarylation reaction of diverse aryl phosphonates
and phosphonamides (Scheme 3). The stereoselectivity of
this reaction was found to be sensitive to the electronic
property of the directing group. The use of phosphonate
esters produced a mixture of olefinic E- and Z-isomers,
while phosphonamides provided the corresponding E-
alkene derivatives 4a, 4b, and 4c stereoselectively in 83%,
72%, and 59% yields, respectively (Scheme 3).
Scheme 5. Dehydrogenative Cross-Coupling of a Phosphonamide
with a Simple Arene
The rhodium-catalyzed oxidative couplings of various
aromatic substrates possessing a directing group with
internal alkynes allows the straightforward synthesis of
benzannulatedheterocyclic compounds from readily avail-
able monofunctionalized aromatic substrates.5 Recent
studies have indicated that a number of heterocycle analo-
gues containing phosphorus show similar bioactivity to
their carbon counterparts. Phosphaisoquinolin-1-ones
may have bioactivities similar to those of isoquinolin-1-
ones, which have gained considerable pharmacological
interest because of their diverse bioactivities. We hoped
to apply the rhodium-catalyzed oxidative cyclization meth-
odology between aromatic phosphonamides and internal
To gain some insight into the mechanism, we conducted
a series of deuteration experiments, looking for H/D scram-
bling to check the reversibility of the CÀH activation step.
Running the olefination and hydroarylation reaction with-
out the acrylate or alkyne using methanol-d4 under other-
wise standard conditions, but with a decreased reaction
time, showed a significant amount of H/D scrambling for
the arylphosphonate (Scheme 6, eq 1) and phosphonamide
4506
Org. Lett., Vol. 15, No. 17, 2013

(Scheme 6, eq 2).9 Running the hydroarylation reaction under
standard conditions, but with a decreased reaction time and
using methanol-d4 as the deuterium source, resulted in sig-
nificant H/D scrambling in the starting material, and the
product of the hydroarylation (Scheme 6, eq 3) could be
observed. These results support that the CÀH activation is
reversible.
Scheme 7. Plausible Mechanism for the Rh(III)-Catalyzed
Olefination and Hydroarylation of Aryl Phosphonates
Scheme 6. Deuteration Experiments Probing the Reversibility
of the CÀH Activation Step
In summary, we have demonstrated that simple arylphos-
phonates and phosphonamides can act as directing
groups in Rh(III) catalysis. Using these phosphoryl-
related directing groups, we developed the rhodium(III)-
catalyzed oxidative CÀH activation of simple arylphos-
phonates and phosphonamides and subsequent coupling
with alkenes (olefination), internal alkynes (hydroaryla-
tion and oxidative cyclization), and simple arenes (CÀH/
CÀH dehydrogenative cross-coupling) to give access to
diverse P-containing frameworks including 2-(1-alkenyl)-
phenylphosphonates, phosphaisoquinolin-1-ones, and biaryl
phosphorus species.
Acknowledgment. This work was supported by the
Alexander von Humboldt Foundation (D.Z.), by “Sus-
tainable Chemical Systems (SusChemSys)” cofinanced by
the European Regional Development Fund (ERDF) and
the state of North Rhine-Westphalia, Germany, under the
Operational Programme “Regional Competitiveness and
Employment” (2007À2013) (C.N.) and by the Deutsche
Forschungsgemeinschaft (SFB 858; M. L.).
Although a more detailed investigation of the reaction
mechanism is currently underway, from these preliminary
mechanistic results weproposed aplausiblecatalytic mech-
anism as illustrated in Scheme 7.4À6 The catalytic process is
initiated by coordination with the phosphoryl-related
directing group to generate the five-membered rhoda-
cycle intermediate A. Subsequently, the seven-membered
rhodacycle intermediate B or C is formed through inser-
tion of alkene or alkyne into the rhodiumÀcarbon bond of
intermediate A. For oxidative cyclization we propose that
PÀNH acts as the directing group to form the five-
membered intermediate, followed by insertion of the
alkyne and oxidative annulation to obtain the product.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) Graczyk, K.; Ma, W.; Ackermann, L. Org. Lett. 2012, 14, 4110.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 17, 2013
4507