Asymmetric assembly of aromatic rings to produce tetra-ortho-substituted axially chiral biaryl phosphorus compounds

Article abstract of DOI:10.1002/anie.200700064

(Chemical Equation Presented) Densely substituted title compounds can be obtained efficiently through an enantioselective [2+2+2] cycloaddition catalyzed by a cationic Rh^I/H₈-binap complex (see scheme). This method is highly practica

Full text of DOI:10.1002/anie.200700064

Angewandte
Chemie
DOI: 10.1002/anie.200700064
Biaryl Synthesis
Asymmetric Assembly of Aromatic Rings To Produce Tetra-ortho-
Substituted Axially Chiral Biaryl Phosphorus Compounds**
Goushi Nishida, Keiichi Noguchi, Masao Hirano, and Ken Tanaka*
Axially chiral biaryl bisphosphine ligands have been
employed widely in asymmetric catalysis, including in the
industrial synthesis of chiral pharmaceuticals and perfumer-
ies.[1] However, frequently bisphosphine ligands can not be
used in transition-metal-catalyzed reactions, as they inhibit
the desired catalytic cycles. To circumvent this limitation,
Uozumi and Hayashi prepared a number of novel axially
chiral biaryl monophosphine ligands,[2] which have since been
applied in a wide variety of catalytic asymmetric reactions.[3]
An enantioselective synthesis of a tri-ortho-substituted
axially chiral biaryl monophosphorus compound through
palladium-catalyzed enantioposition-selective cross-coupling
of an achiral symmetrical biaryl ditriflate with phenylmagne-
sium bromide followed by phosphorus introduction was
developed by Hayashi et al.[4] A more straightforward route,
a catalytic enantioselective aryl–aryl cross-coupling reac-
tion,[5,6] was described by Yin and Buchwald (Scheme 1).[7]
They developed a novel asymmetric Suzuki–Miyaura cross-
coupling of phosphorus-containing aryl halides and aryl
boronic acids; however, this method is restricted to the
synthesis of sterically less demanding tri-ortho-substituted
biaryl phosphonates.[7] The reaction conditions—elevated
temperature (40–808C) and long reaction time (17–48 h)—
and enantioselectivities (57–92% ee) also left room for
improvement. Hence, an efficient catalytic enantioselective
method applicable to the asymmetric synthesis of tetra-ortho-
substituted biaryl monophosphorus compounds with axial
chirality that is thermally more stable toward racemization
would be attractive.
Scheme 1. Synthesis of tri-ortho-substituted axially chiral biaryl phos-
phonates through asymmetric aryl–aryl cross-coupling.
extremely effective for catalytic inter- and intramolecular
[2+2+2] cycloadditions.[8,9] Since this discovery, we have
applied these catalysts in a number of chemo-, regio-, and
enantioselective [2+2+2] cycloadditions,[10–12] including the
synthesis of axially chiral compounds.[12–14] In our previous
enantioselective synthesis of biaryl compounds, the use of
electron-deficient and coordinating alkynes with carbonyl
substituents was highly effective in furnishing axially chiral
biaryl compounds with high ee values.[12] Although the
coordination of carbonyl groups to the cationic rhodium
center enabled high enantioselectivities, the high reactivity of
alkynyl carbonyl compounds toward [2+2+2] homocycload-
dition resulted in lowered yields of the desired [2+2+2] cross-
cycloaddition products. To extend this methodology to the
practical synthesis of axially chiral biaryl phosphorus com-
pounds, we investigated the use of alkynyl phosphonates
instead of alkynyl carbonyl compounds (Scheme 2).[15–17] In
this new approach, the selective introduction of various
substituents, including a phosphorus-centered functional
Our research group first demonstrated that the combina-
tion of cationic rhodium(I) complexes with binap-type ligands
(binap = 2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl)
is
[*] G. Nishida, Dr. M. Hirano, Prof. Dr. K. Tanaka
Department of Applied Chemistry
Graduate School of Engineering
Tokyo University of Agriculture and Technology
Koganei, Tokyo 184-8588 (Japan)
Fax: (+81)42-388-7037
E-mail: tanaka-k@cc.tuat.ac.jp
Prof. Dr. K. Noguchi
Instrumentation Analysis Center
Tokyo University of Agriculture and Technology
Koganei, Tokyo 184-8588 (Japan)
[**] This research was supported partly by the Japan Science and
Technology Agency within the framework of the Collaborative
Development of Innovative Seeds (potentiality verification stage).
We thank Takasago International Corporation for the gift of H8-
binap.
Scheme 2. Synthesis of tetra-ortho-substituted axially chiral biaryl phos-
phonates and phosphine oxides through the asymmetric assembly of
aromatic rings. Cy=cyclohexyl.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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3951

Communications
group, construction of a biaryl skeleton, and introduction of
entry 4) and the tosylamide 1c (entry 5) were suitable
substrates for this transformation. With respect to the
substituent at the 2-position of the 1-alkynyl naphthalene,
the methoxymethoxy and benzyloxy derivatives 2b and 2c
were also suitable substrates for the reaction (Table 1,
entries 6 and 7). Importantly, this method is not restricted to
the synthesis of phosphonates. Both high yields and high
enantioselectivities were observed when the sterically more
demanding diphenylphosphine oxide 2d and dicyclohexyl-
phosphine oxide 2e were employed (Table 1, entries 8–11).[19]
The absolute configuration of the dicyclohexylphosphine
oxide (+)-3ae, synthesized from 1a and 2e, was determined
to be S by the anomalous dispersion method (Figure 1).[20]
axial chirality would be possible in a single step. The reaction
substrates, di-ortho-substituted arylethynyl phosphonates and
phosphine oxides, can be prepared readily through the
Sonogashira coupling of 2,6-disubstituted aryl halides with
terminal alkynes followed by phosphinylation of the alkyne
terminus. These two steps are not influenced by the steric bulk
of the aryl group because of the sterically undemanding linear
geometry of the alkyne. We envisaged that the electron-
deficient and coordinating character of the phosphonyl
moiety would enable high enantioselectivity, and that its
steric bulk would hinder the [2+2+2] homocycloaddition.
We first investigated the asymmetric [2+2+2] cycloaddi-
ton with the readily prepared alkynyl phosphonate 2a derived
from 2-methoxynaphthalene. We were pleased to find that
when a solution of the ether-linked diyne 1a in CH2Cl2 was
added dropwise over 20 min at room temperature to a
solution in CH2Cl2 of 2a and a cationic rhodium(I)/(R)-H8-
binap[18] complex (5 mol%), the tetra-ortho-substituted
axially chiral biaryl phosphonate (À)-3aa was obtained in
quantitative yield with excellent enantioselectivity (Table 1,
entry 1). No reaction was observed upon the treatment of 2a
Table 1: RhI/H8-binap-catalyzed enantioselective [2+2+2] cycloaddition
of symmetrical 1,6-diynes with monoalkynes.
Figure 1. ORTEP diagram of (S)-(+)-3ae (product of Table 1, entry 10;
R1 =Me, R2 =Cy, Z =O). C white, P gray, O black.
The asymmetric [2+2+2] cycloaddition was also applied
to unsymmetrical diynes (Table 2). Diynes 1d and 1e with a
phenyl group and a methyl group or a hydrogen atom at the
alkyne termini reacted with 2a and 2d to give the corre-
sponding biaryl compounds with high enantioselectivities as
single regioisomers 3 (Table 2, entries 1–3). On the other
hand, the diyne 1 f with a methyl group and a hydrogen atom
at the alkyne termini reacted with 2a and 2d to give the
corresponding biaryl compounds in quantitative yield as
separable regioisomers 3 and 4 with good to high enantiose-
lectivities (Table 2, entries 4 and 5). Importantly, remaining
compound 2 could be recovered by chromatography on silica
gel (Table 1, entry 10 and Table 2, entries 1–3).
The synthetic method described herein allows the prep-
aration of a range of new axially chiral biaryl phosphorus
compounds in which the aromatic ring bonded to the
phosphorus atom is highly substituted. These biaryl com-
pounds are not readily accessible by conventional asymmetric
aryl–aryl cross-coupling approaches. Buchwald and co-work-
ers reported recently that the substituents ortho to the
phosphorus center of achiral biaryl monophosphines may
lock the ligand into a certain conformation, which plays an
important role in palladium-catalyzed cross-coupling reac-
tions.[21] Hence, our new axially chiral biaryl phosphorus
compounds may construct a rigid chiral environment and be
applicable in a variety of catalytic asymmetric reactions. The
industrial application of this asymmetric ring-assembly
method to the synthesis of a wide variety of chiral mono-
Entry 1 (Z, equiv)
2 (R1, R2)
Catalyst Yield
[mol%] [%][a]
ee
[%]
1
1a (O, 1.5)
2a (Me, OEt)
2a (Me, OEt)
2a (Me, OEt)
5
5
1
5
5
5
5
5
5
5
5
>99
>99
>99
>99
96
99
>99
92
97 (À)
95 (+)
96 (À)
97 (À)
95 (+)
98 (À)
97 (À)
91 (À)
91 (À)
95 (+)[d]
2[b] 1a (O 1.5)
3
4
5
6
7
1a (O, 1.5)
1b (CH2, 1.5) 2a (Me, OEt)
1c (NTs, 1.0) 2a (Me, OEt)
1c (NTs, 1.0) 2b (CH2OMe, OEt)
1c (NTs, 1.0) 2c (Bn, OEt)
8
9
10
11
1a (O, 1.5)
1b (CH2, 1.5) 2d (Me, Ph)
1a (O, 3.0) 2e (Me, Cy)
1b (CH2, 3.0) 2e (Me, Cy)
2d (Me, Ph)
86
>99
70[c] 96 (+)
[a] Yield of the isolated product. [b] Ligand: (S)-H8-binap. [c] 30% of 2
recovered. [d] S enantiomer. Bn=benzyl, cod=1,5-cyclooctadiene, H8-
binap=2,2’-bis(diphenylphosphanyl)-5,5’,6,6’,7,7’,8,8’-octahydro-1,1’-
binaphthyl, Ts=p-toluenesulfonyl.
with the cationic rhodium(I)/(R)-H8-binap complex, which
confirms the excellent selectivity for the desired [2+2+2]
cross-cycloaddition. Importantly, the use of (S)-H8-binap as a
ligand furnished the opposite enantiomer (Table 1, entry 2).
Furthermore, as the catalytic activity of this rhodium catalyst
is very high, the reaction can even be carried out in the
presence of 1 mol% of the catalyst (Table 1, entry 3).
We tested the generality of the reaction with regard to
both cycloaddition partners. Not only the ether-linked diyne
1a, but also the hydrocarbon-linked diyne 1b (Table 1,
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Table 2: RhI/H8-binap-catalyzed regio- and enantioselective [2+2+2]
cycloaddition of unsymmetrical 1,6-diynes with monoalkynes.
Keywords: alkynes · biaryls · cycloaddition · phosphorus ·
rhodium
.
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Entry 1 (R1, R2, equiv) 2 (R3)
Yield [%][a]
ee [%]
3
4
3
4
1
2
3
4
5
1d (Ph, Me, 1.5) 2a (OEt)
80[b] <1
73[c] <1
34[d] <1
86 (À)
96 (À)
74 (À)
–
–
–
1e (Ph, H, 3.0)
1e (Ph, H, 3.0)
2a (OEt)
2d (Ph)
[7] J. Yin, S. L. Buchwald, J. Am. Chem. Soc. 2000, 122, 12051 –
12052.
1 f (Me, H, 1.5) 2a (OEt)
1 f (Me, H, 3.0) 2d (Ph)
65
54
35
46
93 (+) 87 (À)
58 (À) 86 (À)
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[a] Yield of the isolated product. [b] 20% of 2 recovered. [c] 27% of 2
recovered. [d] 66% of 2 recovered.
and bisphosphorus ligands may also be possible in view of the
ready access to substrates, mild reaction conditions, opera-
tional simplicity, and high catalytic activities.
Experimental Section
Representative procedure (Table 1, entry 2): Under an Ar atmos-
phere, (R)-H8-binap (6.3 mg, 0.010 mmol) and [Rh(cod)2]BF4 (4.1 mg,
0.010 mmol) were dissolved in CH2Cl2 (1.0 mL) in a Schlenk tube, and
the solution was stirred at room temperature for 5 min. H2 (1 atm)
was introduced into the resulting solution, which was then stirred at
room temperature for 1 h. The mixture was concentrated to dryness,
the residue was redissolved in CH2Cl2 (0.4 mL), and a solution of 2a
(318.3 mg, 1.00 mmol) in CH2Cl2 (1.6 mL) was added. A solution of
the diyne 1a (183.2 mg, 1.50 mmol) in CH2Cl2 (3.0 mL) was then
added dropwise over 20 min at room temperature, and the resulting
mixture was stirred at room temperature for 1 h, then concentrated
and purified by column chromatography on silica gel (hexane/EtOAc/
Et3N 3:1:1) to furnish (À)-3aa (439.6 mg, 1.00 mmol, > 99% yield,
97% ee) as a colorless solid. M.p. 77.3–78.98C; [a]2D5 = À22.88 (c =
1
20.8, CHCl3, 97% ee); H NMR (CDCl3, 300 MHz): d = 7.87 (d, J =
8.7 Hz, 1H), 7.82–7.74 (m, 1H), 7.35 (d, J = 9.3 Hz, 1H), 7.30–7.21 (m,
2H), 7.11–7.04 (m, 1H), 5.24 (s, 2H), 5.18 (s, 2H), 3.84 (s, 3H), 3.83–
3.55 (m, 3H), 3.40–3.30 (m, 1H), 2.60 (s, 3H), 1.62 (s, 3H), 1.02 (t, J =
7.2 Hz, 3H), 0.85 ppm (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d = 153.1, 141.8, 141.7, 140.3, 140.1, 138.7, 138.5, 133.7,
133.5, 133.4, 128.8, 128.63, 128.55, 128.45, 128.4, 127.5, 126.0, 125.8,
124.2, 123.32, 123.27, 122.8, 112.5, 74.20, 74.17, 74.1, 60.73, 60.71,
60.66, 60.62, 55.8, 18.81, 18.76, 16.1, 15.8, 15.7, 15.6, 15.5 ppm;
31P NMR (CDCl3, 121 MHz): d = 18.6 ppm; IR (neat): n˜ = 3300, 2900,
1580, 1210, 1020, 960 cmÀ1; HRMS (FAB): m/z calcd for C25H30O5P:
441.1831 [M+H]+; found: 441.1786; HPLC: chiralpak AD-H, hexane/
2-PrOH 90:10, 1.0 mLminÀ1, tR: 8.56 min (major isomer) and 12.9 min
(minor isomer).
Received: January 6, 2007
Published online: April 19, 2007
[14] For asymmetric [2+2+2] cycloadditions developed by other
research groups for the synthesis of axially chiral biaryl
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phosphine oxide can be converted readily into phosphines in
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[20] CCDC-632605 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
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