Rhodium-catalyzed double [2 + 2 + 2] cycloaddition of 1,4- bis(diphenylphosphinoyl)buta-1,3-diyne with tethered diynes: A modular, highly versatile single-pot synthesis of NU-BIPHEP biaryl diphosphines

Article abstract of DOI:10.1021/ol702390p

(Chemical Equation Presented) Rhodium-catalyzed double [2 + 2 + 2] cycloaddition of 1,4-bis(diphenylphosphinoyl)buta-1,3-diyne with tethered diynes provides a straightforward, single-pot procedure for the synthesis of a new class of tropos biaryl diphosph

Full text of DOI:10.1021/ol702390p

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4925-4928
Rhodium-Catalyzed Double [2
Cycloaddition of
+ 2 + 2]
1,4-Bis(diphenylphosphinoyl)buta-1,3-diyne
with Tethered Diynes: A Modular,
Highly Versatile Single-Pot Synthesis of
NU-BIPHEP Biaryl Diphosphines
Simon Doherty,* Julian G. Knight,* Catherine H. Smyth, Ross W. Harrington, and
William Clegg
School of Natural Sciences, Chemistry, Newcastle UniVersity,
Newcastle Upon Tyne NE1 7RU, UK
simon.doherty@ncl.ac.uk
Received October 5, 2007
ABSTRACT
Rhodium-catalyzed double [2
+ 2 + 2] cycloaddition of 1,4-bis(diphenylphosphinoyl)buta-1,3-diyne with tethered diynes provides a straightforward,
single-pot procedure for the synthesis of a new class of tropos biaryl diphosphine, NU-BIPHEP. This methodology represents a significant
improvement on existing multistep procedures. Enantiopure Lewis acid platinum complexes of these diphosphines are highly efficient catalysts
for carbonyl-ene and Diels−Alder reactions, and ruthenium diphosphine-diamine complexes catalyze the asymmetric reduction of ketones to
give ee’s that rival those obtained with their BINAP counterpart.
Tropos and atropos biaryl diphosphines1 are proving to be
a highly versatile and indispensable class of ligand for
platinum group metal asymmetric catalysis;2 recent applica-
tions include the ruthenium-catalyzed asymmetric hydro-
genation of ketones,3 as well as numerous Lewis acid-
catalyzed transformations such as ene cyclizations,4 Diels-
Alder,5 hetero Diels-Alder,6 carbonyl-ene reactions,7 and
Friedel-Crafts alkylations.8 Phosphines of this type are
typically prepared by multistep syntheses involving either a
palladium- or nickel-catalyzed cross-coupling between a
biaryl ditriflate and a secondary phosphine or Ullmann
coupling of a 3-substituted-2-iodophenyl phosphonic acid
dialkylester.1 For use in asymmetric catalysis an atropos
biaryl diphosphine must be either resolved or prepared from
an enantiopure starting material. However, recent develop-
ments in enantioselective aryl-aryl cross-coupling method-
(1) Tropos meaning turn in Greek, refers to axial chiral conformations
that interconvert with a half life of less than 1000 s. Atropos (a meaning
not in Greek) refers to axial chiral conformations which intercovert with a
half life of more than than 1000 s at a given temperature.
(2) (a) Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405.
(b) Berthod, M.; Mignani, G.; Woodward, G.; Lemaire, M. Chem. ReV.
2005, 105, 1801.
(5) Ghosh, A. K.; Matsuda, H. Org. Lett. 1999, 1, 2157.
(6) Oi, S.; Terada, E.; Ohuchi, K.; Kato, T.; Tachibana, Y.; Inoue, Y. J.
Org. Chem. 1999, 64, 8660.
(7) Koh, J. H.; Larsen, A. O.; Gagne´, M. R. Org. Lett. 2001, 3, 1233.
(8) Hao, J.; Taktak, S.; Aikawa, K.; Yusa, Y.; Hatano, M.; Mikami, K.
Synlett 2001, 1443.
(3) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 41.
(4) Fairlamb, I. J. S. Angew. Chem., Int. Ed. 2005, 43, 1048.
10.1021/ol702390p CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/16/2007

ology could present an alternative strategy for the synthesis
of nonracemic biaryl diphosphines, although to date this
approach has been limited to the Suzuki-Miyaura coupling
of phosphonate-based aryl halides with aryl boronic acids.9
In the case of tropos biaryl-based diphosphines, on-metal
resolution and asymmetric activation/deactivation have both
proven to be effective strategies for achieving efficient
asymmetric catalysis.10 In addition, rac-BINAP and BIPHEP-
type diphosphines have also proven to be the ligand of choice
for numerous achiral platinum group metal-catalyzed trans-
formations such as iridium/rhodium-catalyzed C-C bond-
forming hydrogenations,11a chemo- and regioselective inter-
molecular cyclotrimerization of terminal alkynes,11b,c cyclo-
addition and cycloisomerization of 1,6-enynes,11d intra-
molecular amination of aryl bromides.11e and rhodium-
catalyzed isomerization of secondary propargylic alcohols,11f
which further underpins the need to improve the synthesis
of this ligand class. Thus, there is likely to be considerable
interest in developing a more efficient, cost-effective,
straightforward synthesis of biaryl diphosphines, particularly
if it is amenable to the preparation of enantiopure derivatives
and also enables the level and nature of substitution on the
biaryl unit to be varied in a systematic and straighforward
manner.
catalysis,15 we reasoned that chemoselective double [2 + 2
+ 2] cycloaddition between 1,4-bis(diphenylphosphinoyl)-
buta-1,3-diyne (2) and an appropriate 1,n-diyne would afford
substituted BIPHEP diphosphine oxides directly in a single-
pot transformation. Gratifyingly, addition of 1,7-octadiyne
1a (2 equiv) and 2 to a dichloromethane solution of the
cationic rhodium complex generated by abstraction of
chloride from [RhCl(COD)]2 in the presence of rac-BINAP
resulted in complete consumption of the starting material
within 12 h to afford NU-BIPHEP diphosphine oxide 3a in
95% yield, after purification by column chromatography (eq
1).
The same rhodium-catalyzed protocol was successfully
applied to a range of tethered diynes, including those based
on heteroatoms, to give 3a-d in good to excellent yield as
analytically pure off-white solids, after purification by
column chromatography (Table 1). In contrast, the corre-
Herein we report a convenient, highly versatile, modular
single-pot synthesis of tropos biaryl NU-BIPHEP di-
phosphines via chemoselective rhodium-catalyzed double
[2 + 2 + 2] cycloaddition of 1,4-bis(diphenylphosphinoyl)-
buta-1,3-diyne with tethered diynes. Platinum complexes of
these diphosphines have been resolved, and the resulting
enantiopure Lewis acids catalyze the Diels-Alder and
carbonyl-ene reactions, giving excellent levels of enantio-
control. Rhodium- and iridium-catalyzed [2 + 2 + 2]
cycloadditions have recently evolved into a highly efficient
strategy for the synthesis of axially chiral compounds, chiral
spirocyclic structures, and helical polyaryls, with the majority
of contributions originating from the research groups of
Tanaka12 and Shibata13 and more recently Oshima and
Yorimitsu.14 As part of an ongoing program to develop the
synthesis of four-carbon bridged tropos and atropos diphos-
phines for applications in platinum group asymmetric
Table 1. Rhodium-Catalyzed [2 + 2 + 2] Cycloaddition of
1,4-Bis(diphenylphosphinoyl)buta-1,3-diyne with 1,n-Diynesa
entry
1
X
time (h)
product
yieldb (%)
1
2
3
4
5
1a
1b
1c
1d
1e
CH2CH2
CH2
O
C(CO2Me)2
TsN
14
16
14
12
18
3a
3b
3c
3d
3e
95
93
90
96
93
a Reaction conditions: 5 mol % [RhCl(COD)]2, 10 mol % rac-BINAP,
10 mol % AgBF4, 1a-c (3.6 mmol), 2 (1.5 mmol) in 20 mL of CH2Cl2,
room temperature. b Isolated yield.
sponding reaction with 1e resulted in poor conversions
(<5%) which we tentatively suggest to be due to competitive
homo [2 + 2 + 2] cycloaddition of the 1,n-diyne, as
previously described.14 However, a near quantitative yield
of 3e was obtained by slow addition (syringe pump, 6 h) of
a dichloromethane solution of 1e to a catalyst mixture
containing 2. Reduction of the phosphine oxides was
achieved in high yield by heating a THF/toluene solution of
3a-e, trichlorosilane, and triethylphosphite at 100 °C for
48 h to afford the corresponding NU-BIPHEP phosphines
4a-e.
(9) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051.
(10) (a) Mikami, K.; Terada, M.; Korenaga, T.; Matsumoto, Y.; Mat-
sukawa, S. Acc. Chem. Res. 2000, 33, 391. (b) Mikami, K.; Terada, M.;
Korenaga, T.; Matsumoto, Y.; Ueki, M.; Angeland, R. Angew. Chem., Int.
Ed. 2000, 39, 3532.
(11) (a) Ngai, M.-N.; Barchuk, A.; Krische, M. J. J. Am. Chem. Soc.
2007, 129, 280. (b) Tanaka, K.; Yoyoda, K.; Wada, A.; Shirasaka, K.;
Hirano, M. Chem. Eur. J. 2005, 11, 1145. (c) Tanaka, K.; Nishida, G.;
Ogino, M.; Hirano, M.; Noguchi, K. Org. Lett. 2005, 7, 3119. (d) Kezuka,
S.; Okado, T.; Niou, E.; Takeuchi, E. Org. Lett. 2005, 7, 1711. (e) Lebedev,
A. Y.; Khartulyari, A. S.; Voskoboyonikov, A. Z. J. Org. Chem. 2005, 70,
596. (f) Tanaka, K.; Shoji, T. Org. Lett. 2005, 7, 3561.
(12) For selected examples see: (a) Nishida, G.; Noguchi, K.; Hirano,
M.; Tanaka, K. Angew. Chem., Int. Ed. 2007, 46, 3951. (b) Nishida, G.;
Suzuki, N.; Noguchi, K.; Tanaka, K. Org. Lett. 2006, 8, 3489. (c) Wada,
A.; Noguchi, K.; Hirano, M.; Tanaka, K. Org. Lett. 2007, 9, 1295. (d)
Tanaka, K.; Osaka, T.; Noguchi, K.; Hirano, M. Org. Lett. 2007, 9, 1307.
(13) For selected examples see: Tsuchikama, K.; Kuwata, Y.; Shibata,
T. J. Am. Chem. Soc. 2006, 128, 13686. (b) Shibata, T.; Fujimoto, T.;
Yokota, K.; Takagi, K. J. Am. Chem. Soc. 2004, 126, 8382. (c) Shibata, T.;
Tsuchikama, K.; Otsuka, M. Tetrahedron: Asymmetry 2006, 17, 614.
(14) Kondoh, A.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2007,
129, 6996.
(15) (a) Doherty, S.; Knight, J. G.; Robins, E. G.; Scanlan, T. H.;
Champkin, P. A.; Clegg, W. J. Am. Chem. Soc. 2001, 123, 5110. (b)
Doherty, S.; Newman, C. R.; Rath, R. K.; van den Berg, J.-A.; Hardacre,
C.; Nieuwenhuyzen, M.; Knight, J. G. Organometallics 2004, 23, 1055.
(c) Doherty, S.; Newman, C. R.; Rath, R. K.; Luo, H.-K.; Nieuwenhuyzen,
M.; Knight, J. G. Org. Lett. 2003, 5, 3863. (d) Doherty, S.; Knight, J. G.;
Hardacre, C.; Luo, H.-K.; Newman, C. R.; Rath, R. K.; Campbell, S.;
Nieuwenhuyzen, M. Organometallics 2004, 23, 6127. (e) Doherty, S.;
Goodrich, P.; Hardacre, C.; Luo, H.-K.; Nieuwenhuyzen, M.; Rath, R. K.
Organometallics 2005, 24, 5945.
4926
Org. Lett., Vol. 9, No. 23, 2007

X-ray quality crystals of 4a were obtained by slow
diffusion of a chloroform solution layered with methanol at
room temperature, the structure of which is shown in Figure
1.16
it was first necessary to identify an appropriate resolution
procedure. In this regard, various ligands have emerged as
effective resolving agents for platinum group metal com-
plexes of tropos diphosphines, including enantiopure BINOL,
2,2′-diaminobinaphthyl (DABN) and its derivatives as well
as 1,2-diphenylethylenediamine (DPEN). By analogy with
early studies on BIPHEP,17 we chose to prepare λ- and
δ-[(4a)Pt{(S)-BINOL}] (7a) which was initially obtained as
a near 1:1 mixture of diastereoisomers from the reaction
between rac-[(4a)PtCl2] (6a)18 and (S)-Na2-BINOLate in
THF/toluene (1:1). Thermolysis of a toluene solution of this
mixture resulted in diastereointerconversion and near quan-
titative precipitation of the thermodynamically favored
diastereopure δ-[(4a)Pt{(S)-BINOL}], which was converted
into the corresponding enantiopure dichloride δ-6a, by
treatment of a dichloromethane solution with 2 equiv of HCl.
The stereochemistry of δ-6a was assigned by analysis of the
absolute configurations of the products obtained from the
benchmark carbonyl-ene19 and Diels-Alder reactions de-
scribed below. In the first of these, the Lewis acid fragment
generated by treatment of a dichloromethane solution of δ-6a
with 2 equiv of silver hexafluoroantimonate catalyzes the
carbonyl-ene reaction between a range of allylbenzene
derivatives, 8a-f, and ethyl trifluoropyruvate to give the
corresponding R-hydroxy esters 9a-f in good yield, complete
E-selectivity, and exceptionally high enantioselectivity (Table
2). The absolute configuration of R-hydroxy ester 9a was
Figure 1. Structure of one of the two crystallographically
inequivalent molecules of 4a with 40% probability ellipsoids.
In an attempt to extend this methodology to include the
synthesis of highly substituted NU-BIPHEP diphosphines
from internal diynes, the reaction between 2,8-decadiyne and
2 was investigated. While there was no evidence for
cycloaddition under the same conditions as those used to
prepare 3a-e even after 24 h at room temperature, the same
reaction in chlorobenzene at 100 °C resulted in selective
mono [2 + 2 + 2] cycloaddition to afford 5 in near quantitive
yield, based on consumption of 2 (eq 2). The identity of 5
Table 2. Asymmetric Carbonyl-ene Reactions Catalyzed by
δ-[(4a)Pt](SbF6)2 in CH2Cl2 at Room Temperaturea
entry
product
X
conversion (%)
% ee
1
was initially established by a combination of 31P, H, and
1
2
3
4
5
6b
9a
9b
9c
9d
9e
9f
H
4-Me
2-Cl
3-Cl
4-Cl
67
63
71
66
60
98
99
99
99
99
>99
99
13C NMR spectropscopy and mass spectrometry and ulti-
mately confirmed by a single-crystal X-ray study. Although
this reaction clearly shows that double cycloaddition of
internal diynes is a much more challenging transformation,
the unreacted alkynyl phosphine oxide in adducts of type 5
could provide an ideal template for the synthesis of unsym-
metrical biaryl diphosphines by reaction either with a
terminal 1,n-diyne or an ynenitrile.
4-NO2
a Reaction conditions: 5 mol % catalyst, allylbenzene (0.4 mmol), ethyl
trifluoropyruvate (0.6 mmol) in 2.0 mL of CH2Cl2. b 24 h.
determined by comparison of the optical rotation with that
reported in the literature,20 and those of 9b-f were assigned
by analogy.
(17) Becker, J. J.; White, P. S.; Gagne´, M. R. J. Am. Soc. 2001, 123,
9478.
(18) Full details of the single-crystal X-ray analysis of rac-6a are given
in the Supporting Information.
(19) (a) Mikami, K.; Kakuno, H.; Aikawa, K. Angew. Chem., Int. Ed.
2005, 44, 7257. (b) Doherty, S.; Knight, J. G.; Smyth, C. H.; Harrington,
R. W.; Clegg, W. J. Org. Chem. 2006, 71, 9751.
(20) (a) Mikami, K.; Aikawa, K.; Kainuma, S.; Kawakami, Y.; Saito,
T.; Sayo, N.; Kumobayashi, H. Tetrahedron: Asymmetry 2004, 15, 3885.
(b) Aikawa, K.; Kainuma, S.; Hatano, M.; Mikami, K. Tetrahedron Lett.
2004, 45, 183.
In order to evaluate the potential of these new biaryl
diphosphines in platinum group metal asymmetric catalysis
(16) Full details of the single-crystal X-ray analysis of 4a are given in
the Supporting Information.
Org. Lett., Vol. 9, No. 23, 2007
4927

The same Lewis acid also catalyzes the Diels-Alder
reaction between N-acryloyl-oxazolidinone and cyclopenta-
diene (eq 3) to afford cycloadduct 2R-(10) with high endo
selectivity (93:7 endo:exo) and excellent endo enantioselec-
tivity (99%). The absolute configuration of the products
obtained from these benchmark reactions is the same as that
obtained with (S)-BINAP and its derivatives, which was used
as the basis for the assignment of a δ, S-like, stereochemistry
to enantiopure 6a (vide supra). Catalyst reaction mixtures
were routinely quenched immediately prior to workup by
addition of 1 equiv of (S,S)-DPEN. In each case the 31P NMR
spectrum showed the presence of a single diastereisomer
(1JPt-P ) 3453 Hz), confirming that the stereochemical
integrity of the Lewis acid remains intact under the reaction
conditions.
diphosphines with a variety of substitution patterns and
functionalities. This highly modular synthesis overcomes
many of the limitations associated with the conventional
methods of preparation such as the palladium- and nickel-
catalyzed phosphination, which can result in monosubstitu-
tion, and low-yielding bromination-lithiation procedures.
Studies are currently underway to explore the range of
alkynylphosphines that undergo double [2 + 2 + 2]
cycloaddition, develop this methodology to include the
enantioselective synthesis of chiral NU-BIPHEP diphos-
phines from internal 1,n-diynes, prepare unsymmetrical
derivatives, and to determine whether cycloaddition occurs
via a seven-membered metalacycloheptatriene or a metal-
anorbornene intermediate.22
Biaryl diphosphines have also been widely investigated
for the ruthenium-catalyzed asymmetric hydrogenation of
ketones,21 which prompted us to investigate the efficiency
of these new ligands in this transformation. A preliminary
study revealed that the 1:1 diastereoisomeric mixture of
[RuCl2(4a){(S,S)-DPEN}] (11a) forms a highly active cata-
lyst for the asymmetric hydrogenation of acetophenone (0.1
mol % catalyst, >99% conversion in 12 h), giving the
corresponding alcohol with R absolute configuration in 58%
ee (eq 4), a significant improvement on that of 46% obtained
with the corresponding catalyst based on rac-BINAP and
(S,S)-DPEN.21
Acknowledgment. We gratefully acknowledge the EPSRC
for funding (CHS, Newcastle University) and Johnson
Matthey for generous loans of platinum group metal salts.
Supporting Information Available: Experimental details
and characterization data for compounds 3a-e, 4a-e, 5, 6a,
7a, 9b-f, and 11a, details of catalyst testing, and for
compounds 4a and rac-6a details of crystal data, structure
solution and refinement, atomic coordinates, bond distances
and angles and anisotropic displacement parameters in CIF
format. This material is available free of charge via the
Internet at http://pubs.acs.org.
In conclusion, [2 + 2 + 2] cycloaddition of 1,4-bis-
(diphenylphosphinoyl)buta-1,3-diyne with 1,n-diynes pro-
vides a versatile single-pot synthesis of NU-BIPHEP biaryl
OL702390P
(22) (a) Kezuka, S.; Tanaka, S.; Ohe, T.; Nakaya, Y.; Takeuchi, R. J.
Org. Chem. 2006, 71, 543. (b) Agenet, N.; Gandon, V.; Vollhardt, K. P.
C.; Malacria, M.; Aubert, C. J. Am. Chem. Soc. 2007, 129, 8860.
(21) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.;
Noyori, R. Angew. Chem., Int. Ed. 1999, 38, 495.
4928
Org. Lett., Vol. 9, No. 23, 2007