Rhodium-catalyzed regioselective olefin hydrophosphorylation

Article abstract of DOI:10.1021/ol016989r

(Matrix Presented) Parameters influencing the selectivity of the (PPh₃)₃RhCl-catalyzed hydrophosphorylation of olefins and enynes are described. The reaction between differentiated dienes was shown to be highly responsive to olefin substitution. The trimethylsilyl group effectively reversed the normal preference for hydrophosphorylation of an alkyne over an alkene.

Full text of DOI:10.1021/ol016989r

ORGANIC
LETTERS
2
001
Vol. 3, No. 26
303-4306
Rhodium-Catalyzed Regioselective
Olefin Hydrophosphorylation
4
John F. Reichwein, Mittun C. Patel, and Brian L. Pagenkopf*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
pagenkopf@mail.utexas.edu
Received November 1, 2001
ABSTRACT
3 3
Parameters influencing the selectivity of the (PPh ) RhCl-catalyzed hydrophosphorylation of olefins and enynes are described. The reaction
between differentiated dienes was shown to be highly responsive to olefin substitution. The trimethylsilyl group effectively reversed the
normal preference for hydrophosphorylation of an alkyne over an alkene.
New methods for phosphonate synthesis continue to attract
attention because phosphonates display biologically important
properties as natural products, analogues of phosphates
reactions is important. In this regard, Tanaka recently
reported the palladium(II)-catalyzed hydrophosphorylation
of terminal and strained cyclic olefins with the pinacol-
1
2
3
4
8-0
(
including RNA/DNA), phosphonopeptides, amino acid
derived phosphonite 1 (Scheme 1).
5
6
analogues, and pro-drugs. The number of methods for the
preparation of organophosphonates is limited, and tradition-
ally phosphonates are prepared by Arbuzov reaction of
A significant advantage of transition metal catalyzed olefin
hydrophosphorylations over traditional phosphonate synthesis
is the mild reaction conditions. However, to successfully
predict the effectiveness of the reaction in the context of a
complex synthetic target with multiple sites of unsaturation,
information regarding the selectivity of the olefin hydro-
phosphorylation is required. In addition to defining the
parameters that influence the selectivity between differenti-
ated olefins, the effect and compatibility with other func-
tionalities such as amides and vinyl ethers need to be
addressed. Currently, the major drawback of the hydrophos-
phorylation reaction shown in Scheme 1 is its dependence
7
phosphites with organic halides. Given the indispensable
utility of phosphonates as bioactive molecules and synthetic
tools (e.g., Wadsworth-Emmons and related reactions),
research into the synthesis of phosphonates and associated
(
(
1) For a review, see: Fields, S. C. Tetrahedron 1999, 55, 12237-12273.
2) For a review, see: Blackburn, M. G. Chem. Ind. (London) 1981,
1
34-144.
(
3) For reviews, see: (a) Eckstein, F.; Thomson, J. B. Methods Enzymol.
1
1
2
995, 262, 189-202. (b) Egli, M. Angew. Chem., Int. Ed. Engl. 1996, 35,
894-1909. (c) De Clercq, E. Biomed. Pharmacother. 1996, 50, 207-
15.
2 2 2 4 2
upon cis-PdMe (PPh (CH ) PPh ) as catalyst, which is air-
(
4) For a review, see: Failla, S.; Finocchiaro, P.; Consiglio, G. A.
Heteroat. Chem. 2000, 11, 493-504. For a recent report: Rushing, S. D.;
Hammer, R. P. J. Am. Chem. Soc. 2001, 123, 4861-4862.
(8) Han, L.-B.; Mirzaei, F.; Zhao, C.-Q.; Tanaka, M. J. Am. Chem. Soc.
2000, 122, 5407-5408.
(
5) Kafarski P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Prod. 1991,
6
3, 193-215.
6) For a review, see: Krise, J. P.; Stella, V. J. AdV. Drug DeliVery ReV.
996, 19, 287-310.
7) (a) Organic Phosphorus Compounds; Kosolapoff, G. M., Maier, L.,
(9) Radical olefin hydrophosphorylation is known: Stiles, A. R.;
Vaughan, W. E.; Rust, F. F. J. Am. Chem. Soc. 1958, 80, 714-716.
(10) Alkyne hydrophosphorylation was reported previously, see: (a) Han,
L.-B.; Zhao, C.-Q.; Tanaka, M. J. Org. Chem. 2001, 66, 5929-5932. (b)
Han, L.-B.; Hua, R.; Tanaka, M. Angew. Chem., Int. Ed. Engl. 1998, 37,
94-96. (c) Han, L.-B.; Choi, N. R.; Tanaka, M. Organometallics 1996,
15, 3259-3261. (d) Zhao, C.-Q.; Han, L.-B.; Goto, M.; Tanaka, M. Angew.
Chem., Int. Ed. 2001, 40, 1929-1932.
(
1
(
Eds.; Wiley-Interscience: New York, 1972. (b) Handbook of Organophos-
phorus Chemistry; Engel, R., Ed.; Marcel Dekker: New York, 1992. (c)
Corbridge, D. E. C. Phosphorus: An Outline of Its Chemistry, Biochemistry
and Uses, 5th ed.; Elsevier: Amsterdam, 1995.
1
0.1021/ol016989r CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/05/2001

Scheme 1
11
sensitive and not commercially available. A better catalyst
would be commercially available, more robust and relatively
air-stable. In this communication we disclose that Wilkin-
and reproducible hydrophosphorylation with low catalyst
loading (1.25 mol % rhodium, entry 5). Substituting DPPB
with more economical phosphines either had no effect on
son’s catalyst, (PPh
3
)
3
RhCl, efficiently catalyzes olefin
turnover versus Wilkinson’s catalyst alone (Ph
3
P, entry 6)
n
hydrophosphorylation and describe the effect of alkene and
alkyne substitution on the selectivity of the reaction.
A preliminary screening of various metal species in
or fully attenuated catalyst activity ( Bu P, entry 7).
3
With an active and convenient rhodium catalyst in hand,
an investigation into its ability to differentiate between two
dissimilar olefins was initiated. To determine whether subtle
electronic effects could direct the hydrophosphorylation,
diene 4 was treated with 0.9 equiv of 1 under the new
dioxane at 100 °C, including Pd(PPh
PPh RhCl, revealed that each catalyzed the hydrophos-
phorylation of 1-octene 2 in the presence of hydrogen
3 4 2 3
) , Pd (dba) , and
(
3 3
)
12
13
16
phosphite 1, albeit in moderate yields (Table 1). However,
catalysis conditions (Scheme 2). The products 5a, 5b, and
Table 1. Effect of Metal Catalyst and Additives on the
Hydrophosphorylation Reaction 1 + 2 f 3a
Scheme 2
yieldd
entry
catalyst
mol %
additive
(%)
1b
2c
3c
4b
5c
6b
7b
8b
9b
(PPh3)3RhCl
(PPh3)3RhCl
(PPh3)3RhCl
(PPh3)3RhCl
(PPh3)3RhCl
(PPh3)3RhCl
(PPh3)3RhCl
(PPh3)3RhCl
Pd(PPh3)4
5
5
2.5
1.25
1.25
5
5
5
5
2.5
57
95
91
85 (99)e
99
42
nrf
5% DPPB
2.5% DPPB
1.25% DPPB
5% DPPB
10% Ph3P
n
10% Bu3P
5% DPPB, 150% DMF 96
37
1
0b
Pd2(dba)3
5% DPPB
25
a
Reactions were performed at 100 °C in 1,4-dioxane under an atmosphere
of Ar. One milimole scale. Ten milimole scale. Isolated yields. e After
additional DPPB.
b
c
d
1
5 f
No reaction.
5
3
c were obtained in a 1.3:1:1 ratio, and therefore only a small
:1 preference existed for reaction at the allylic position.
2 2 4 2 ,
in the presence of Ph P(CH ) PPh (DPPB) Wilkinson’s
14
catalyst gave excellent yields (entry 2, 95%). The formation
of DPPB oxides during the course of the reaction suggested
that DPPB might serve to reduce a catalytically inactive
oxidized rhodium species. In entry 4 the reaction failed to
go to completion, but the stalled reaction resumed upon
addition of additional DPPB.15 In this regard, the addition
of more than 1 equiv of DPPB per rhodium allowed efficient
Additionally, isomerization of the bis-homoallylic olefin to
an internal position occurred in 5c. Similar yield and product
distributions were observed with tosamide 6.
While substrates 4 and 6 showed that a subtle electronic
difference between olefins was insufficient to significantly
17
control the regioselectivity of the hydrophosphorylation,
the catalyst was adept at distinguishing between disubstituted
and monosubstituted olefins, as summarized in Table 2. In
the competition between a terminal olefin and a stereochemi-
cally pure trans olefin (entry 1), reaction occurred only at
the sterically more accessible position, and the stereochemical
integrity of the trans olefin remained intact. In entry 2
complete regiocontrol was also observed, but in this instance
(
11) de Graaf, W.; Boersma, J.; Smeets, W. J. J.; Spek, A. L.; van Koten,
G. Organometallics 1989, 8, 2907-2917.
12) The use of HP(O)Ph2 and HP(O)(OEt)2 failed in the reaction. Details
will be described elsewhere.
(
(
13) Similar results have been observed; see ref 8.
(14) Although reactions were typically assembled in an inert atmosphere
glovebox, the use of Wilkinson’s catalyst that had been stored exposed to
air for weeks performed equally well provided 2 equiv of DPPB per Rh
was added to the reaction.
(
15) The reaction mixture was yellow throughout the initial period of
(16) General Experimental Procedure. A round-bottomed flask was
charged with the olefin (1.1 equiv), hydrogen phosphonate 1 (1.0 equiv),
2.5 mol % (PPh3)3RhCl, 5 mol % DPPB, and dioxane (0.25 M). The reaction
mixture was heated at 100 °C for 20 h and then concentrated in vacuo. The
phosphonates were purified by flash chromatography on silica gel.
the reaction but turned orange/brown before complete consumption of
phosphonate 1 (85% yield from one-half of the reaction). After 2 mol %
additional DPPB was added to the reaction, the yellow color returned and
the reaction proceeded to completion.
4304
Org. Lett., Vol. 3, No. 26, 2001

Table 2. Selective Hydrophosphorylation
stereochemical scrambling to the trans olefin 10b occurred
in half of the product. Isomerization of the cis olefin suggests
a close interaction with the rhodium catalyst, but no internal
hydrophosphorylation was detected. In entry 3, preference
for the terminal olefin over the 2,2-disubstituted alkene was
observed. Attempts to achieve hydrophosphorylation at the
remaining site of unsaturation in 12 by employing an excess
of hydrogen phosphonate 1 were unsuccessful. In entry 4,
the internal olefin is in conjugation with a phenyl ring, and
this had no impact on the selectivity or yield of the reaction.
In entry 5, only hydrophosphorylation was observed at the
terminal olefin, and the low 56% yield was accredited to
phorylation of alkynes versus monosubstituted olefins. To
address this deficiency, treatment of enyne 17 under the
1
6
standard reaction conditions gave the E vinyl phosphonate
18a as a single regio- and stereoisomer from hydrophos-
phorylation exclusively at the triple bond (Scheme 3).
Importantly, substitution of the terminal alkyne with a
trimethylsilyl protecting group (n-BuLi, THF, -78 °C;
3
Me SiCl, 96%) resulted in a reversal of reactivity and only
the olefin underwent hydrophosphorylation (19 f 20b). The
TMS protecting group allows access to the terminal alkyne
for further functionalization, as it can be easily removed with
2 3 4
methanolic K CO or Bu NF. In contrast to the impressive
18
the instability of the product that decomposed on standing.
While alkyne hydrophosphorylation is well documented,
regioselectivity observed in the above experiments, competi-
tive hydrophosphorylation with enynes 21 and 23 gave
complex mixtures of regio- and stereoisomers (Scheme 4).
10
no reports have appeared on the selectivity of hydrophos-
Scheme 3
Org. Lett., Vol. 3, No. 26, 2001
4305

Scheme 4
In summary, we have reported that (PPh
3
)
3
RhCl in the
reliably converted to their aliphatic phosphonates in the
presence of other olefins. Additionally, a trimethylsilyl group
is an effective acetylene protecting functionality that reverses
the normal preference for alkyne hydrophosphorylation over
a terminal olefin.
presence of DPPB is an efficient catalyst for the hydrophos-
phorylation of olefins.19 The reaction is highly sensitive to
olefin substitution, and monosubstituted olefins can be
(17) To explore whether more significant electronic effects would
influence the hydrophosphorylation of a monosubstituted olefin, the vinyl
ether 25, a substrate that offers an attractive synthetic handle for further
synthetic modifications, was exposed to our standard reaction conditions.16
This gave rather disappointing results, but by increasing both the catalyst
loading and the reaction time (2 d) a 70% yield of the â-benzyloxy
phosphonate 26 was obtained.
Acknowledgment. We thank the Robert A. Welch
Foundation and the DOD Prostate Cancer Research Program
DAMD17-01-1-0109 for financial support of our work.
M.C.P. thanks the University of Texas at Austin for an
undergraduate research fellowship.
Supporting Information Available: Spectral data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL016989R
(
18) Palladium-catalyzed hydrophosphorylation of dienes has been
reported: Miraei, F.; Han, L.-B.; Tanaka, M. Tetrahedron Lett. 2001, 42,
97-299.
(19) The use of pinacol-derived phosphonates in Horner-like coupling
reactions will be described elsewhere.
2
4306
Org. Lett., Vol. 3, No. 26, 2001