The concise synthesis of chiral tfb ligands and their application to the rhodium-catalyzed asymmetric arylation of aldehydes

Article abstract of DOI:10.1039/b911118b

New C₂-symmetric tetrafluorobenzobarrelene ligands were prepared and applied successfully to the rhodium-catalyzed asymmetric addition of arylboronic acids to aromatic aldehydes giving chiral diarylmethanols in high yield with high enantioselectivity.

Full text of DOI:10.1039/b911118b

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The concise synthesis of chiral tfb ligands and their application
to the rhodium-catalyzed asymmetric arylation of aldehydeswz
Takahiro Nishimura,* Hana Kumamoto, Makoto Nagaosa and Tamio Hayashi*
Received (in College Park, MD, USA) 5th June 2009, Accepted 27th July 2009
First published as an Advance Article on the web 17th August 2009
DOI: 10.1039/b911118b
New C2-symmetric tetrafluorobenzobarrelene ligands were
prepared and applied successfully to the rhodium-catalyzed
asymmetric addition of arylboronic acids to aromatic aldehydes
giving chiral diarylmethanols in high yield with high enantio-
selectivity.
Chiral dienes have recently been developed as a new class of
chiral ligands for transition metals, realizing highly efficient
and enantioselective reactions.1 Of diene ligands bearing diverse
bicyclic skeletons, tetrafluorobenzobicyclo[2.2.2]octatriene
(tetrafluorobenzobarrelene; tfb; 1a) and its derivatives2 are
attractive compounds because of their high coordination
ability toward transition metals due to their small bite angle
and electron-deficient character.3 In addition, the synthesis of
tfb dienes is easy; e.g. tfb 1a is prepared in one step by the
formal [4 + 2]-cycloaddition of benzene with tetrafluorobenzyne
generated from pentafluorophenyl-lithium or -magnesium
(Scheme 1, route a).2 The use of 1,4-disubstituted benzenes
provides chiral tfb dienes. Recently, we reported the synthesis
of enantiomerically-pure disubstituted tfb dienes (1b and 1c)
via the cycloaddition of tetrafluorobenzyne with 1,4-disubstituted
benzenes, and their application to rhodium- and iridium-
catalyzed asymmetric additions of arylboronic acids.4 One
drawback of the direct preparation of chiral tfb dienes is the
difficulty of synthesizing tfbs 1 substituted with aromatic
groups. Provided that enantiopure ditriflate 2 is obtained, it
is possible to prepare diverse chiral tfb dienes by transition
Scheme
2
Synthesis of C2-symmetric tetrafluorobenzobarrelenes
(tfb*).
metal-catalyzed cross-coupling reactions (route b). Here,
we report the development of C2-symmetric disubstituted
tetrafluorobenzobicyclo[2.2.2]octatrienes 1 and their successful
application to the rhodium-catalyzed asymmetric arylation of
aldehydes with arylboronic acids.
Chiral ditriflate 2 and tfb ligands 1d–f were prepared
through straightforward pathways (Scheme 2). The [4 + 2]-
cycloaddition of 1,4-diisopropoxybenzene to tetrafluorobenzyne,
followed by hydrolysis, gave dl-3 in 40% yield.5 The resolution
of diketone dl-3 by the use of a chiral stationary phase column
(Chiralpak IA)6 gave both enantiomers (+)-3 and (ꢀ)-3,
which were transformed into ditriflate 2.7 Enantiopure
ditriflate 2 was subjected to cross-coupling reactions with
benzylmagnesium chloride,8 phenylboronic acid9 and ferrocenyl-
zinc chloride,10 leading to 1d, 1e and 1f, respectively, in good
yields. The reaction of chiral dienes 1d–f with [RhCl(C2H4)2]2
gave rhodium complexes [RhCl(1)]2 in high yields (Scheme 3).
The absolute configuration of (S,S)-1f was assigned by the
X-ray crystallographic analysis of its rhodium complex
Rh(1f)[(Z6-C6H5)BPh3] (Scheme 3, Fig. 1).11
Scheme 1 Tetrafluorobenzobarrelenes (tfbs).
Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo, Kyoto 606-8502, Japan.
E-mail: tnishi@kuchem.kyoto-u.ac.jp, thayashi@kuchem.kyoto-u.ac.jp;
Fax: +81 75 753 3983; Tel: +81 75 753 3988
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. CCDC 734763. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b911118b
The asymmetric synthesis of diarylmethanols by the enantio-
selective arylation of aldehydes remains a very important
objective in organic synthesis.12 A successful development
has been achieved in the asymmetric addition of arylzinc
reagents to aldehydes by the use of chiral ligands.13
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 5713–5715 | 5713

Table 1 The asymmetric addition of 6m to 5aa
Yield
(%)b
ee
Entry
Ligand
Solvent
(%)c
1
2
3
4
5
6
7
8
1b
1c
1d
1e
4
1f
1f
1f
1f
1f
1,4-Dioxane/H2O (4 : 1)
1,4-Dioxane/H2O (4 : 1)
1,4-Dioxane/H2O (4 : 1)
1,4-Dioxane/H2O (4 : 1)
1,4-Dioxane/H2O (4 : 1)
1,4-Dioxane/H2O (4 : 1)
Methanol
2-Propanol
tert-Butyl alcohol
tert-Butyl alcohol
25d
30d
49d
94
94
94
99
99
94
95
16 (S)
43 (S)
27 (S)
49 (S)
49 (S)
72 (S)
78 (S)
84 (S)
86 (S)
86 (S)
Scheme 3 Synthesis of rhodium complexes.
9
10e
a
Reaction conditions: [RhCl(diene)]2 (3.75 mmol, 3 mol% of Rh),
5a (0.25 mmol), 6m (0.50 mmol), KOH (0.38 mmol), solvent (1.0 mL),
b
c
30 1C, 12 h. Isolated yield. Determined by HPLC analysis with a
chiral stationary phase column (Chiralcel OD-H). Unreacted 5a was
d
e
observed. Performed with [RhCl((S,S)-1f)]2 (1 mol% of Rh) for 3 h.
Fig. 1 ORTEP illustration of Rh((S,S)-1f)[(Z6-C6H5)BPh3] with
thermal ellipsoids drawn at the 50% probability level. The solvent
molecule (CH2Cl2) and hydrogens are omitted for clarity.
Table
2
The asymmetric addition of arylboronic acids (6) to
aromatic aldehydes 5a
The transition metal-catalyzed asymmetric addition of organo-
metallic reagents to aldehydes is another useful method for the
synthesis of chiral diarylmethanols, where arylboronic acids
are used as attractive arylating reagents. Since the first report
of the rhodium-catalyzed asymmetric arylation of aldehydes
by Miyaura et al. in 1998,14a Rh,1k,14 Ni15 and Ru16-catalyzed
reactions have been developed.
Yield
(%)b
Entry Ar1
Ar2
ee (%)c
1
2
3
4
5
6
7
8
9
10
1-Naphthyl (5a)
2-ClC6H4 (5b)
2-BrC6H4 (5c)
2-MeOC6H4 (5d)
2-MeC6H4 (5e)
3-MeC6H4 (5f)
4-MeC6H4 (5g)
4-BrC6H4 (5h)
2-Naphthyl (5i)
Ph (6m)
Ph (6m)
Ph (6m)
Ph (6m)
Ph (6m)
Ph (6m)
Ph (6m)
Ph (6m)
Ph (6m)
95 (7am) 86 (S)
97 (7bm) 84 (S)
95 (7cm) 84 (S)
99 (7dm) 85 (S)
98 (7em) 86 (S)
96 (7fm) 80 (S)
99 (7gm) 78 (S)
85 (7hm) 78 (S)
93 (7im) 82 (S)
94 (7jm) 79 (S)
The new rhodium complexes with tfb ligands, 1d–1f, were
tested in the asymmetric arylation of aldehydes with arylboronic
acids. Ligands 1b, 1c and Ph-bod 41c,d were also used for
comparison. The treatment of 1-naphthaldehyde (5a) with
phenylboronic acid (6m) in the presence of [RhCl(1b)]2
(3 mol% of Rh) and KOH (1.5 equiv.) in 1,4-dioxane/H2O
(4 : 1) at 30 1C for 12 h gave diarylmethanol 7am in low yield
and ee (25%, 16% ee) (Table 1, entry 1). The yields of 7am
were also low in the reaction when tfb ligands substituted with
alkyl groups were used (1c and 1d; Table 1, entries 2 and 3).
On the other hand, Ph-tfb* 1e displayed a higher catalytic
activity and enantioselectivity, giving 7am in 94% yield with
49% ee (Table 1, entry 4). The same yield and enantio-
selectivity were observed in the reaction using Ph-bod* 4,
which has phenyl groups on a bicyclo[2.2.2]octadiene skeleton
(Table 1, entry 5). These results imply that the electron-
deficient character of the diene substituted with phenyl groups
improves the catalytic activity. A higher enantioselectivity was
obtained with the tfb ligand 1f (Fc-tfb*) substituted with
ferrocenyl groups, where the ee of 7am was 72% (Table 1,
entry 6). The reaction solvents had a significant influence on
the enantioselectivity. Thus, reactions in protic solvents
improved the ee of 7am (Table 1, entries 7–9), and the highest
enantioselectivity (86% ee) was observed in tert-butyl alcohol
(Table 1, entry 9). The reaction with a catalyst loading of
3,4-(OC2H4O)C6H3 Ph (6m)
(5j)
11
Ferrocenyl (5k)
1-Naphthyl (5a)
1-Naphthyl (5a)
1-Naphthyl (5a)
1-Naphthyl (5a)
1-Naphthyl (5a)
1-Naphthyl (5a)
Ph (6m)
94 (7km) 85 (S)
12
3,5-Me2C6H3 (6n) 90 (7an) 87 (S)d
13e
14
4-MeC6H4 (6o)
3-MeC6H4 (6p)
2-MeC6H4 (6q)
2-ClC6H4 (6r)
90 (7ao) 85 (S)
93 (7ap) 87 (S)d
87 (7aq) 91 (S)
91 (7ar) 86 (R)d
15e
16e
17e
2-MeO-5-MeC6H3 97 (7as) 85 (R)d
(6s)
18e
1-Naphthyl (5a)
2,6-(MeO)2C6H3
(6t)
80 (7at) 84 (R)d
19e
20e
21e
22e
23e
24e
1-Naphthyl (5a)
2-ClC6H4 (5b)
2-MeC6H4 (5e)
2-BrC6H4 (5c)
Ferrocenyl (5k)
Ferrocenyl (5k)
Mesityl (6u)
Mesityl (6u)
Mesityl (6u)
2-MeC6H4 (6q)
Mesityl (6u)
2-MeC6H4 (6q)
87 (7au) 94 (R)
70 (7bu) 94 (S)d
87 (7eu) 93 (R)d
87 (7cq) 86 (S)d
85 (7ku) 84 (S)d
98 (7kq) 86 (S)
Reaction conditions: [RhCl((S,S)-1f)]2 (1 mol% of Rh), Ar1CHO
a
(0.25 mmol), Ar2B(OH)2 (0.50 mmol), KOH (0.38 mmol), t-BuOH
b
3 h. Isolated yield. Determined by HPLC
c
(1.0 mL), 30 1C,
analysis. The absolute configuration was assigned by analogy with
d
e
entry 1. Performed with [RhCl((S,S)-1f)]2 (3 mol% of Rh) for 12 h.
ꢁc
This journal is The Royal Society of Chemistry 2009
5714 | Chem. Commun., 2009, 5713–5715

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Scheme 4 The asymmetric double arylation of 8.
1 mol% rhodium was complete within 3 h (Table 1, entry 10).
The absolute configuration of 7am, produced by the use of
(S,S)-1f, was determined to be (S) by comparisons of its
specific rotation and retention time in chiral HPLC with those
values reported previously.14
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Table 2 summarizes the results obtained for the reactions of
several aldehydes 5 with arylboronic acids 6, which were
carried out in the presence of [RhCl((S,S)-Fc-tfb*(1f))]2
(1 or 3 mol% of Rh). The scope of the aldehydes was broad,
examples variously substituted with electron-withdrawing
groups and electron-donating groups were good substrates
and produced diarylmethanols in high yields (Table 2,
entries 1–11). Enantioselectivities in the phenylation of
aldehydes having ortho-substituents (Table 2, entries 1–5) on
the benzene ring were higher than those obtained with meta-
or para-substituted aromatic aldehydes (Table 2, entries 6–9).
The scope of arylboronic acids was also broad (Table 2,
entries 12–24), where the use of ortho-substituted arylboronic
acids displayed higher enantioselectivities of diarylmethanols 7
(Table 2, entries 13–15 for MeC6H4B(OH)2). Thus, the present
catalytic system is effective for the asymmetric synthesis of
diarylmethanols having ortho-substituents on both aromatic
rings, the enantioselectivity ranging between 84 and 94% ee
(Table 2, entries 15–22). The asymmetric double arylation of
isophthalaldehyde (8) was also successful, using mesityl-
boronic acid (6u) to give a 98% ee of chiral diol 9 (75% yield,
chiral : meso = 85 : 15) (Scheme 4).17
6 A semi-preparative column (2.0 cm ID ꢂ 25 cm) was used for the
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This work was supported by a Grant-in-Aid for Scientific
Research (S) (19105002) from the MEXT, Japan.
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ꢁc
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Chem. Commun., 2009, 5713–5715 | 5715