Palladium-catalyzed hydrophosphorylation and hydrophosphinylation of cyclopropenes

Article abstract of DOI:10.1021/ol8011138

(Chemical Equation Presented) Novel transition-metal-catalyzed addition of P-H entities across the cyclopropene double bond has been developed. This transformation allows for mild and efficient preparation of phosphorus- containing cyclopropanes in good y

Full text of DOI:10.1021/ol8011138

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3231-3234
Palladium-Catalyzed
Hydrophosphorylation and
Hydrophosphinylation of Cyclopropenes
Bassam K. Alnasleh, William M. Sherrill, and Michael Rubin*
Department of Chemistry, UniVeristy of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-75832
mrubin@ku.edu
Received May 14, 2008
ABSTRACT
Novel transition-metal-catalyzed addition of P-H entities across the cyclopropene double bond has been developed. This transformation
allows for mild and efficient preparation of phosphorus-containing cyclopropanes in good yields and high degrees of diastereoselectivity.
Phosphorus-containing cyclopropanes are an important class
of compounds with great potential for both medicinal
chemistry and organic synthesis. Thus, derivatives of cyclo-
propylphosphonic acid make attractive targets for drug
discovery, as they are omnipresent among biologically active
compounds including antiproliferative,1 antiviral,2 and an-
timalarial3 agents. Phosphorylated cyclopropanes also hold
great promise as potential selective herbicides.4 Furthermore,
cyclopropylphosphines have been shown to serve as efficient
ligands in several transition-metal-catalyzed transformations.5
The existing approaches to cyclopropylphosphorus com-
pounds span various modes of [2 + 1] cycloaddition,6
MIRC,7 and related 1,3-cyclizations.8 They can also be
obtained by derivatization of the pre-existing cyclopropane
moiety, including reactions of P-nucleophiles with cyclo-
propanone equivalents9 or P-electrophiles with cyclopropy-
lmetals.5,10 The efficiency of these methods, however,
dramatically decreases with the increase of steric demand at
the cyclopropyl core. Recently, we11 and Marek12 developed
an alternative approach to cyclopropylphosphorus compounds
via a formal [2,3]-rearrangement of cyclopropenylmeth-
ylphosphinites, which permits synthesis of densely substituted
methylenecyclopropylphosphine oxides (Scheme 1, eq 1).
In light of this finding, we wondered whether addition of
a phosphorus entity to the double bond of cyclopropene could
also be achieved in an intermolecular fashion via a direct
hydrophosphorylation (Scheme 1, eq 2).13 It should be
(6) (a) Barluenga, J.; Fernandez-Rodriguez, M. A.; Garcia-Garcia, P.;
Aguilar, E.; Merino, I. Chem.-Eur. J. 2005, 12, 303. (b) Reddy, R. P.;
Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8, 3437. (c) Slootweg, J. C.;
de Kanter, F. J. J.; Schakel, M.; Lutz, M.; Spek, A. L.; Kozhushkov, S. I.;
de Meijere, A.; Lammertsma, K. Chem.-Eur. J. 2005, 11, 6982. (d)
Charette, A. B.; Bouchard, J.-E. Can. J. Chem. 2005, 83, 533. (e) Ferrand,
Y.; Le Maux, P.; Simonneaux, G. Org. Lett. 2004, 6, 3211. (f) Davies,
H. M. L.; Lee, G. H. Org. Lett. 2004, 6, 2117. (g) Krysiak, J.; Lyon, C.;
Baceiredo, A.; Gornitzka, H.; Mikolajczyk, M.; Bertrand, G. Chem.-Eur.
J. 2004, 10, 1982. (h) Slootweg, J. C.; Schakel, M.; de Kanter, F. J. J.;
Ehlers, A. W.; Kozhushkov, S. I.; de Meijere, A.; Lutz, M.; Spek, A. L.;
Lammertsma, K. J. Am. Chem. Soc. 2004, 126, 3050. (i) Despagnet, E.;
Gornitzka, H.; Rozhenko, A. B.; Schoeller, W. W.; Bourissou, D.; Bertrand,
G. Angew. Chem., Int. Ed. 2002, 41, 2835. (j) Moore, J. D.; Sprott, K. T.;
Hanson, P. R. J. Org. Chem. 2002, 67, 8123. (k) Midura, W. H.;
Mikolajczyk, M. Tetrahedron Lett. 2002, 43, 3061.
(1) Minutolo, F.; Asso, V.; Bertini, S.; Betti, L.; Ciriaco, M.; Danesi,
R.; Gervasi, G.; Ghilardi, E.; Giovanetti, E.; Giannaccini, G.; Placanica,
G.; Prota, G.; Rapposelli, S.; Macchia, M. Med. Chem. 2005, 1, 239.
(2) See, for example: (a) Zhou, S.; Brietenbach, J. M.; Borysko, K. Z.;
Drach, J. C.; Kern, E. R.; Gullen, E.; Cheng, Y.-C.; Zemlicka, J. J. Med.
Chem. 2004, 47, 566. (b) Yan, Z.; Zhou, S.; Kern, E. R.; Zemlicka, J.
Tetrahedron 2006, 62, 2608.
(3) Devreux, V.; Wiesner, J.; Goeman, J. L.; van der Eycken, J.; Jomaa,
H.; van Calenbergh, S. J. Med. Chem. 2006, 49, 2656.
(4) (a) Asada, T.; Aoki, T.; Masui, M.; Nakaida, Y.; Yasushi, Y.;
Yamamoto, I. JP 02001460. (b) Hayakawa, K.; Mori, I.; Iwasaki, G.;
Matsunaga, S. EP 528760. (c) Cox, J. M.; Bellini, P.; Barret, R.; Ellis,
R. M.; Hawkes, T. R. WO9315610.
(5) Molander, G. A.; Burke, J. P.; Carroll, P. J. J. Org. Chem. 2004,
69, 8062.
10.1021/ol8011138 CCC: $40.75
Published on Web 06/28/2008
2008 American Chemical Society

Scheme 1
Table 1. Optimization of the Reaction Conditionsa
mentioned that, while a plethora of different additions of
various metallic species across the CdC bond of cyclopro-
pene have been developed, additions of nonmetallic entities
with preservation of the three-membered carbocycle have
represented a significant challenge.14 Thus, Yamamoto
demonstrated that palladium-catalyzed additions of C- and
N-pronucleophiles to dialkylcyclopropene proceed with ring
opening, affording allylmalonates and allylamine deriva-
tives.15 A single example of transition-metal-catalyzed ad-
dition of a carbon pronucleophile to cyclopropene proceeding
with preservation of a three-membered ring was recently
shown by Chisholm.16 Herein, we report an efficient and
atom-economic approach to cyclopropylphosphonates and
cyclopropylphosphine oxides via the diastereoselective pal-
ladium-catalyzed hydrophosphorylation and hydrophosphi-
nylation of cyclopropenes.17
We began our optimization by testing the reaction between
3-methyl-3-phenylcyclopropane (1a) and 4,4,5,5-tetramethyl-
2-oxo-1,3,2-dioxaphospholane (2) (eq 3). It was found that
thermal and radically initiated reactions did not proceed at
all; however, formation of hydrophosphorylation products
was observed in the presence of several Pd catalysts (Table
1). Yet, most catalytic systems tested provided very sluggish
reactions with moderate facial selectivity. Furthermore, the
no.
R
catalyst
4, % (trans/cis)b 3, %b
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(π-allylPdCl)2/TTMPPc
(π-allylPdCl)2/PPh3
Pd(OAc)2/TTMPP
Pd(OAc)2/PPh3
Pd2dba3·CHCl3/TTMPP
Pd2dba3·CHCl3/dppe
Pd2dba3·CHCl3/dppf
Pd(PPh3)4
60 (2.5:1)
7 (N/D)
45 (15:1)
30 (4.5:1)
13 (N/D)
NR
98 (4:1)
89 (19:1)
100 (3:1)
97 (9:1)
10
-
40
34
-
-
-
6
CO2Me Pd(PPh3)4
-
-
10 CO2Me Pd2dba3·CHCl3/dppf
a Reactions performed on a 0.1 mmol scale. b GC conversion, n-octane
wasusedasaninternalstandard.c TTMPP:tris(2,4,6-trimethoxyphenyl)phosphine.
reaction was complicated by the formation of a side product,
allylphosphonate 3 (Table 1). Our attempts to accelerate the
addition by increasing the reaction temperature resulted in a
marked shift toward formation of the ring opening product
3. Gratifyingly, employment of Pd(PPh3)4 allowed the desired
phosphonate 4a with very high diastereo- and chemoselec-
tivity to be accessed (entry 8).
A putative mechanism for this transformation is shown in
Scheme 2. First, oxidative addition of palladium into the
(7) MIRC - Michael-Initiated Ring Closure. See, for example: (a)
Swamy, K. C. K.; Kumar, K. V. P. P.; Suresh, R. R.; Kumar, N. S. Synthesis
2007, 1485. (b) Waszkuc, W.; Janecki, T. Org. Biomol. Chem. 2003, 1,
2966. (c) Stevens, C. V.; Van Heecke, G.; Barbero, C.; Patora, K.; De
Kimpe, N.; Verhe, R. Synlett 2002, 1089.
Scheme 2
. Mechanistic Rationale for the Pd-Catalyzed
Hydrophosphorylation of Cyclopropenes
(8) (a) Zeuner, F.; Angermann, J.; Moszner, N. Synth. Commun. 2006,
36, 3679. (b) Odinets, I. L.; Vinogradova, N. M.; Lyssenko, K. A.;
Petrovskii, P. V.; Mastryukova, T. A.; Roschenthaler, G.-V. Heteroatom
Chem. 2006, 17, 13.
(9) Tesson, N.; Dorigneux, B.; Fadel, A. Tetrahedron: Asymmetry 2002,
13, 2267.
(10) Buron, C.; Tippmann, E. M.; Platz, M. S. J. Phys. Chem. A 2004,
108, 1033.
(11) Rubina, M.; Woodward, E. W.; Rubin, M. Org. Lett. 2007, 9, 5501.
(12) Masarwa, A.; Stanger, A.; Marek, I. Angew. Chem., Int. Ed. 2007,
46, 8093.
(13) For Pd-catalyzed hydrophosphorylation of olefins, see, for example:
(a) Xu, Q.; Han, L.-B. Org. Lett. 2006, 8, 2099. (b) Han, L.-B.; Mirzaei,
F.; Zhao, C.-Q.; Tanaka, M. J. Am. Chem. Soc. 2000, 122, 5407.
(14) For recent reviews see, for example: (a) Rubin, M.; Rubina, M.;
Gevorgyan, V. Chem. ReV. 2007, 107, 3117. (b) Rubin, M.; Rubina, M.;
Gevorgyan, V. Synthesis 2006, 1221. (c) Fox, J. M.; Yan, N. Curr. Org.
Chem. 2005, 9, 719.
(15) Nakamura, I.; Bajracharya, G. B.; Yamamoto, Y. J. Org. Chem.
2003, 68, 2297.
(16) Yin, J.; Chisholm, J. D. Chem. Commun. 2006, 632.
(17) For noncatalyzed additions of phosphorus species to 1,2-dichloro-
cyclopropenes, see: (a) Svara, J.; Fluck, E. Chem.-Zeit. 1985, 109, 11. For
Diels-Alder reaction of cyclopropene with 1,3,5-triphosphabenzene, see:
(b) Peters, C.; Disteldorf, H.; Fuchs, E.; Werner, S.; Stutzmann, S.;
Bruckmann, J.; Kruger, C.; Binger, P.; Heydt, H.; Regitz, M. Eur. J. Org.
Chem. 2001, 3425.
3232
Org. Lett., Vol. 10, No. 15, 2008

Table 2. Palladium-Catalyzed Hydrophosphorylation of 3,3-Disubstituted Cyclopropenes
a Relative configuration of a major diastereomer is shown. b Isolated yields of a major diastereomer. c Isolated yield of two diastereomers. d THF was
used as a solvent.
P-H bond produces palladium hydride species 6. Subsequent
migratory instertion of cyclopropene 1 affords cyclopropy-
lpalladium complex 7 (Scheme 2).18 The latter, upon
reductive elimination (path A), produces cyclopropylphos-
phonate 4. This reaction is syn-specific, as demonstrated by
the hydrophosphorylation of deuterium-labeled cyclopropene
1a-d2 (eq 4).19
Alternatively, at higher temperatures, species 7 would
undergo ring cleavage via ꢀ-carbon elimination (path B).14a
The resulting 3η-allylpalladium species 8 would afford, after
reductive elimination, allylphosphonate 3.
With the optimized conditions in hand, we moved on to
investigate the scope of the new hydrophosphorylation
reaction. It was disappointing to discover that methyl ester
1b provided only marginal diastereoselectivity in the pres-
ence of Pd(PPh3)4 (Table 1, entry 9). Further optimization
revealed that the Pd2(dba)3·CHCl3-dppf combination, which
appeared to be an inferior catalyst for the 3-methyl-3-
phenylcyclopropene 1a (Table 1, entry 7), provided a much
better trans/cis ratio with the ester-substituted substrate 1b
(Table 1, entry 10). Other ester-containing cyclopropenes
1c,d afforded the corresponding products with equally high
diastereoselectivities (Table 2, entries 3 and 4). In contrast
to the phenyl-substituted analog 1a, all esters reacted
(18) It was demonstrated that the diastereoselectivity of this process is
temperature-dependent. See Supporting Information for details.
(19) See Supporting Information for details.
Org. Lett., Vol. 10, No. 15, 2008
3233

smoothly at ambient temperature, providing complete con-
version within 1-2 h (Table 2, entries 2-7). Diastereose-
lectivity of hydrophosphorylation was mainly controlled by
sterics, as evident from the comparison of the results obtained
using 1-methyl-substituted cyclopropenylcarboxylates 1b-d
(entries 2-4) with those of the 1-phenyl- (entry 5) and
1-TMS-substituted analogs (entry 6). Indeed, while the
reactions of cyclopropenes 1a-d predominantly provided
products 4a-d in a trans-configuration, introduction of the
bulky phenyl substituent in the structure (1e) led to a
significant deterioration of the diastereoselectivity (entry 5).
Finally, installation of an even larger TMS group (1f) resulted
in reversal of diastereoselectivity, affording cyclopropyl
phosphonate 4f with the phosphorus moiety oriented cis with
respect to the ester function.
Scheme 3
.
Palladium-Catalyzed Hydrophosphinylation of
Cyclopropenesa
a Reaction conditions. 6e: 1 h at 25 °C; 6j: 48 h at 55 °C; 6k: 78 h at
50 °C.
We further examined the hydrophosphorylation reaction
on a series of 3-carboxamidocyclopropenes 1h-k (Table 2,
entries 8-11). It was found that, in contrast to cycloprope-
nylcarboxylates, amides 1h-k reacted more sluggishly and
required prolonged heating at 50-55 °C. Nonetheless, the
corresponding products 4h-k were obtained in good yields
with high to excellent diastereoselectivities (Table 2, entries
7-10).
Inspired by the success in the catalytic hydrophosphory-
lation, we explored the possibility of addition of diorga-
nylphosphine oxides to cyclopropenes.20 Gratifyingly, the
conditions optimized for hydrophosphorylation also proved
efficient for the hydrophosphinylation reaction (Scheme 3).
The reactivity pattern was similar to that observed in the
hydrophosphorylation reaction. Thus, ester 1e underwent the
transformation quickly at room temperature, while reaction
of amides 1j and 1k required extended heating at 50-55 °C
for complete conversion. Importantly, in all three cases, the
corresponding cyclopropylphosphine oxides 6e,j,k were
obtained in excellent yield as single diastereomers (Scheme 3).
In conclusion, a novel, efficient transition-metal-catalyzed
method for diastereoselective addition of cyclic phosphites
and phosphine oxides across the strained double bond of
cyclopropene was developed. This transformation is ap-
plicable to a wide range of 3,3-disubstituted cyclopropenes
and is general with respect to the electronic nature of the
P-H entity. The discovered method has great potential for
providing expeditious access to a series of novel function-
alized cyclopropylphosphonic acids and cyclopropylphos-
phines. Studies on the possibility of carrying out this reaction
in an asymmetric fashion is currently underway in our
laboratories.
(20) For leading references on transition-metal-catalyzed hydrophos-
phinylation of alkenes and alkynes, see: (a) Niu, M.; Fu, H.; Jiang, Y.;
Zhao, Y. Chem. Commun. 2007, 272. (b) Van Rooy, S.; Cao, C.; Patrick,
B. O.; Lam, A.; Love, J. A. Inorg. Chim. Acta 2006, 359, 2918. (c) Ribiere,
P.; Bravo-Altamirano, K.; Antczak, M. I.; Hawkins, J. D.; Montchamp,
J.-L. J. Org. Chem. 2005, 70, 4064. (d) Allen, A., Jr.; Ma, L.; Lin, W.
Tetrahedron Lett. 2002, 43, 3707. (e) Deprele, S.; Montchamp, J.-L. J. Am.
Chem. Soc. 2002, 124, 9386. (f) Han, L.-B.; Zhao, C.-Q.; Onozawa, S.;
Goto, M.; Tanaka, M. J. Am. Chem. Soc. 2002, 124, 3842. (g) Han, L.-B.;
Zhao, C.-Q.; Tanaka, M. J. Org. Chem. 2001, 66, 5929. (h) Hua, R.; Tanaka,
M. Chem. Lett. 1998, 431. (i) Han, L.-B.; Hua, R.; Tanaka, M. Angew.
Chem., Int. Ed. 1998, 37, 94.
Acknowledgment. We thank the University of Kansas and
the National Science Foundation (EEC-0310689) for financial
support.
Supporting Information Available: Experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL8011138
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Org. Lett., Vol. 10, No. 15, 2008