Palladium-catalyzed propargylic substitution with phosphorus nucleophiles: Efficient, stereoselective synthesis of allenylphosphonates and related compounds

Article abstract of DOI:10.1021/ol102121j

A new, efficient method is developed, based on a palladium(0)-catalyzed reaction of propargylic derivatives with various phosphorus nucleophiles, to produce allenylphosphonates and their analogues with defined stereochemistry in the allenic and the phosph

Full text of DOI:10.1021/ol102121j

ORGANIC
LETTERS
2
010
Vol. 12, No. 20
702-4704
Palladium-Catalyzed Propargylic
Substitution with Phosphorus
Nucleophiles: Efficient, Stereoselective
Synthesis of Allenylphosphonates and
Related Compounds
4
†
Marcin Kalek, Tommy Johansson, Martina Jezowska, and Jacek Stawinski*
†
†
,†,‡
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm UniVersity,
S-106 91 Stockholm, Sweden, and Institute of Bioorganic Chemistry, Polish Academy
of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland
js@organ.su.se
Received September 6, 2010
ABSTRACT
A new, efficient method is developed, based on a palladium(0)-catalyzed reaction of propargylic derivatives with various phosphorus nucleophiles,
to produce allenylphosphonates and their analogues with defined stereochemistry in the allenic and the phosphonate moiety.
In recent years, allenes have rapidly evolved from curious
chemical entities into one of the most flourishing research
subjects in organic chemistry. An allene structural motif
hence can serve as very useful synthetic intermediates.
Synthesis of allenylphosphonates has been dominated by
[2,3]-sigmatropic rearrangement of propargyl phosphites,
1
1,7
has been discovered in many natural products and has started
2
to attract increasing attention of pharmaceutical research.
(4) Ma, S.; Lu, P.; Lu, L.; Hou, H.; Wei, J.; He, Q.; Gu, Z.; Jiang, X.;
Jin, X. Angew. Chem., Int. Ed. 2005, 44, 5275–5278. Piera, J.; N a¨ rhi, K.;
B a¨ ckvall, J.-E. Angew. Chem., Int. Ed. 2006, 45, 6914–6917. Piera, J.;
Persson, A.; Caldentey, X.; Backvall, J.-E. J. Am. Chem. Soc. 2007, 129,
3
Due to the development of novel synthetic methods, allenes
also became useful intermediates in chemical synthesis, often
enabling a rapid molecular complexity increase in a single
1
4120–14121. Inagaki, F.; Sugikubo, K.; Miyashita, Y.; Mukai, C. Angew.
Chem., Int. Ed. 2010, 49, 1–6
(5) Hoffman-R o¨ der, A.; Krause, N. Angew. Chem., Int. Ed. 2002, 41,
2933–2935. Bongers, N.; Krause, N. Angew. Chem., Int. Ed. 2008, 47, 2178–
.
4
reaction step, inter alia, due to an efficient transfer of
1
,5
chirality to the newly formed stereocenters.
2
181
6) Chakravarty, M.; Swamy, K. C. K. J. Org. Chem. 2006, 71, 9128–
138. Khusainova, N. G.; Mostovaya, O. A.; Berdnikov, E. A.; Litvinov,
.
(
A special class of allenes constitute allenylphosphonates
9
6
and related compounds that exhibit diverse reactivity and
I. A.; Krivolapov, D. B.; Cherkasov, R. A. Russ. J. Org. Chem. 2005, 41,
260–1264. Santos, J. M.; L o´ pez, Y.; Aparicio, D.; Palacios, F. J. Org.
1
Chem. 2008, 73, 550–557. Mukai, C.; Ohta, M.; Yamashita, H.; Kitagaki,
S. J. Org. Chem. 2004, 69, 6867–6873. Brel, V. K.; Belsky, V. K.; Stash,
A. I.; Zavodnik, V. E.; Stang, P. J. Eur. J. Org. Chem. 2005, 512–521.
Chakravarty, M.; Swamy, K. C. K. Synthesis 2007, 3171–3178. Gu, Y.;
Hama, T.; Hammond, G. B. Chem. Commun. 2000, 395–396. Zapata, A. J.;
†
Stockholm University.
Polish Academy of Sciences.
‡
(
1) Modern Allene Chemistry; Krause, N., Hashimi, A. S. K., Eds.;
Wiley-VCH: Weinheim, 2004.
2) Hoffman-R o¨ der, A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43,
196–1216.
3) Ma, S. Chem. ReV. 2005, 105, 2829–2871. Sydnes, L. K. Chem.
ReV. 2003, 103, 1133–1150.
(
Gu, Y.; Hammond, G. B. J. Org. Chem. 2000, 65, 227–234.
1
(7) Boisselle, A. P.; Meinhardt, N. A. J. Org. Chem. 1962, 25, 1828–
1833. Pudovik, A. N.; Aladzheva, I. M. J. Gen. Chem. USSR (Engl. Transl.)
(
1963, 33, 700–701
.
1
0.1021/ol102121j  2010 American Chemical Society
Published on Web 09/20/2010

which has a broad scope with respect to the precursor
propargylic alcohols used, enabling the synthesis of alle-
nylphosphonates with various substitution patterns in the
allene moiety. Despite these, the approach suffers from a
serious drawback, namely, a limit in the kind of substituent
that can be attached to the phosphonate center.
Table 1. Synthesis of Allenylphosphonates and Related
Compounds
a
To overcome this limitation and to explore new avenues
to carbon-phosphorus bond formation, we turned our
attention to a completely unexplored, in this context, transi-
tion-metal-catalyzed propargylic substitution (S 2′) reaction
N
as a means of synthesis of allenylphosphonates. Although
this is a well established synthetic approach to a variety of
1,8
allenes, the reaction has never been used for the formation
of the C-P bond. We expected that stereoselectivity and
chirality transfer from the propargylic substrate observed
1
during some allene synthesis would also be preserved for
phosphorus nucleophiles. Since other Pd-catalyzed C-P
9
bond-forming reactions have been shown to work well in
the synthesis of biologically important phosphorus com-
1
0
pounds, and mechanistic aspects of the reaction with aryl
1
1
electrophiles have been studied in depth, we expected that
these may lend themselves to a new method for the
construction of complex allenylphosphonate derivatives.
Herein we report for the first time studies on a palladium-
catalyzed propargylic substitution reaction with H-phospho-
nates and related compounds as nucleophiles. Our aim was
to develop a new synthetic method for this class of
compounds and expand the scope of accessible allenylphos-
phonates, particularly those of potential biochemical rel-
evance.
As a model reaction we chose coupling between propargyl
chloride and diethyl H-phosphonate (Table 1, entry 1). The
screening revealed that only bidentate ligands with wide bite
angles were able to promote a conversion into the alle-
nylphosphonate, and the highest reaction rate was observed
for bis(2-phenylphosphinophenyl)ether (DPEPhos) (see Sup-
porting Information).
a
Reagents and conditions: 1.38 mmol of propargylic substrate, 1.25
The scope of the reaction turned out to be broad in terms
of propargyl derivatives and the H-phosphonates used, as it
was apparent from synthesis of allenylphosphonates with
diverse structural features (Table 1).
mmol of P-nucleophile, 0.019 mmol (1.5 mol %) of Pd
mmol (3 mol %) of DPEPhos, 5 mL of THF (0.25 M), 68 °C. For
propargylic chlorides, additionally 1.5 mmol of Et N.
2
(dba)
3
3
·CHCl , 0.038
3
In this reaction propargyl chlorides showed relatively high
reactivity that did not depend on the presence or absence of
substituents at C1 (Table 1, entry 1 vs 3 and 8). Propargyl
carbonates did not require an external base and exhibited
significant differences in rates between primary vs secondary
substrates (entry 2 vs 4), with the latter one reacting much
faster (7 h vs 30 min). A substituent in the terminal position
(
8) Ma, S. Eur. J. Org. Chem. 2004, 1175–1183. Tsuji, J.; Mandai, T.
Angew. Chem., Int. Ed. 1995, 34, 2589–2612
9) Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron
002, 58, 2041–2075. Schwan, A. L. Chem. Soc. ReV. 2004, 33, 218–224.
Montchamp, J. L. J. Organomet. Chem. 2005, 690, 2388–2406.
10) Abbas, S.; Hayes, C. J. Synlett 1999, 7, 1124–1126. Abbas, S.;
.
(
2
3
of the alkyne (R ) dramatically slowed down the reaction
(
for both the leaving groups, and a good conversion to the
corresponding allenylphosphonate could only be achieved
for the carbonate derivative (entry 5 vs 6). However,
introduction of substituents at C1 significantly increased
the reactivity of this type of substrate (entries 7 and 9). The
coupling reaction was sensitive to steric hindrance at the
phosphorus center as it is apparent from entry 10 vs 1 in
Table 1. Other phosphorus nucleophiles, e.g., phosphinate
esters, could also be used in this reaction (entries 11-13) to
produce the corresponding allenylphosphinates. Although the
last two products could also technically be obtained using
Bertram, R. D.; Hayes, C. J. Org. Lett. 2001, 3, 3365–3367. Johansson, T.;
Stawinski, J. Chem. Commun. 2001, 2564–2565. Lav e´ n, G.; Stawinski, J.
Collect. Symp. Ser. 2005, 7, 195–199. Kalek, M.; Stawinski, J. Collect.
Symp. Ser. 2008, 10, 214–218. Kalek, M.; Ziadi, A.; Stawinski, J. Org.
Lett. 2008, 10, 4637–4640. Kalek, M.; Jezowska, M.; Stawinski, J. AdV.
Synth. Catal. 2009, 351, 3207–3216.
(
11) Kalek, M.; Stawinski, J. Organometallics 2007, 26, 5840–5848.
Kalek, M.; Stawinski, J. Organometallics 2008, 27, 5876–5888. Levine,
A. M.; Stockland, R. A.; Clark, R.; Guzei, I. Organometallics 2002, 21,
3
278–3284. Stockland, R. A.; Levine, A. M.; Giovine, M. T.; Guzei, I. A.;
Cannistra, J. C. Organometallics 2004, 23, 647–656. Kohler, M. C.;
Stockland, R. A., Jr.; Rath, N. P. Organometallics 2006, 25, 5746–5756.
Kohler, M. C.; Grimes, T. V.; Wang, X.; Cundari, T. R.; Stockland, R. A.
Organometallics 2009, 29, 1193–1201.
Org. Lett., Vol. 12, No. 20, 2010
4703

1
,7
the sigmatropic rearrangement reaction, preparation of
suitable tervalent phosphorus precursors would pose con-
siderable difficulty. On the other hand, aryl- and vinylphos-
phinates used in our palladium-catalyzed propargylic sub-
stitution reaction can be easily synthesized by methods
Scheme 2
1
2
develped by Montchamp et al.
To investigate the stereochemistry of this reaction, enan-
tioenriched propargyl carbonates 1 were allowed to react with
diethyl H-phosphonate 2 under the developed conditions. As
is apparent from the results in Scheme 1, propargyl carbon-
Scheme 1
is important to mention that this aspect of the allenylphos-
phonates synthesis, i.e., control of stereochemistry at the
phosphorus atom, is completely beyond the scope of the
1
,7
original sigmatropic rearrangenent method.
In conclusion, we have developed a novel method for the
synthesis of allenylphosphonates and related compounds via
a Pd(0)-catalyzed coupling of propargylic derivatives with
H-phosphonate diesters or their analogues. The reaction
represents a new means for the formation of the C-P bond
and permits stereoselective and stereospecific construction
of an allenic moiety with complete transfer of center to axial
chirality and retention of configuration at the phosphorus
center. By a proper choice of propargylic components and
H-phosphonate derivatives, complex organic structures can
be generated. High efficiency, mildness of the reaction
conditions, and easily accessible starting materials can make
this reaction a method of choice for the synthesis of various
analogues of biologically important compounds with a
predefined stereochemistry and substitution pattern in the
allene and the phosphonate moieties.
ates (R)-1 and (S)-1 were transformed into allenylphospho-
nates 3 in a completely stereoselective and stereospecific
manner.
Center to axis chirality transfer described above does not
exhaust stereochemical features of this allenylphosphonate
synthesis. The other equally important aspect is chirality at
the phosphorus center. Therefore we studied a stereochemical
course of the investigated reaction, when the starting material
contained a stereogenic phosphorus center (Scheme 2).
To this end, two diastereomeric dinucleoside H-phospho-
nates, with opposite configurations at the phosphorus, (R
and (S )-4, were subjected separately to coupling with
propargyl chloride under the developed reaction conditions
Scheme 2). It was found that each of the dinucleoside 4
diastereomers was transformed quantitatively into the cor-
responding diastereomer of the product [Scheme 2, (R )-5
and (S )-5), respectively], and this proved that the palladium-
P
)-4
P
(
Acknowledgment. Financial support from the Swedish
Natural Science Research Council is gratefully acknowl-
edged.
P
P
catalyzed process was completely stereospecific, and the
configuration at the phosphorus center in the product was
determined by the configuration in the starting material. It
Supporting Information Available: Synthetic experi-
mental procedures, ligand screening results, characterization
data for all the compounds, and NMR spectra of synthesized
allenylphosphonates. This material is available free of charge
via the Internet at http://pubs.acs.org.
(
12) Dumond, Y. R.; Baker, R. L.; Montchamp, J. L. Org. Lett. 2000,
2
1
8
, 3341–3344. Montchamp, J. L.; Dumond, Y. R. J. Am. Chem. Soc. 2001,
23, 510–511. Bravo-Altamirano, K.; Montchamp, J.-L. Org. Lett. 2006,
, 4169–4171.
OL102121J
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