The first asymmetric Sonogashira coupling for the enantioselective generation of planar chirality in paracyclophanes

Article abstract of DOI:10.1039/b818904h

The double Sonogashira coupling of diiodoparacyclophanes with alkynes proceeded to give planarly chiral dialkynylparacyclophanes; a chiral Pd catalyst, which was prepared in situ from PdCl₂(CH ₃CN)₂ and Taniaphos, realized the first asymmetric Sonogashira coupling with up to ca. 80% ee.

Full text of DOI:10.1039/b818904h

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COMMUNICATION
www.rsc.org/chemcomm | ChemComm
The first asymmetric Sonogashira coupling for the enantioselective
generation of planar chirality in paracyclophanesw
Kazumasa Kanda, Tamami Koike, Kohei Endo and Takanori Shibata*
Received (in College Park, MD, USA) 24th October 2008, Accepted 14th January 2009
First published as an Advance Article on the web 24th February 2009
DOI: 10.1039/b818904h
The double Sonogashira coupling of diiodoparacyclophanes with
alkynes proceeded to give planarly chiral dialkynylparacyclo-
phanes; a chiral Pd catalyst, which was prepared in situ from
PdCl2(CH3CN)2 and Taniaphos, realized the first asymmetric
Sonogashira coupling with up to ca. 80% ee.
Pd-catalyzed cross couplings are some of the most conven-
tional and reliable carbon–carbon bond forming reactions,1
and they have made a significant contribution to the synthesis
of complex molecules with various functionalities.2 They can
be categorized into patterns of couplings, such as Csp2–Csp2
,
Fig. 1 Our concept of asymmetric Sonogashira coupling.
Csp2–Csp3, Csp–Csp2, and so on. The asymmetric versions,
which use chiral Pd catalysts, have been a challenging topic
in asymmetric synthesis.3 The pioneering work in this area was
the dynamic kinetic resolution of the reaction between
secondary alkyl metal reagents and vinyl or aryl halides; the
coupling of a Grignard reagent with a vinyl bromide
(Csp3–Csp2 coupling) generated an asymmetric carbon center.4
Enantioselective desymmetrization is a different approach;5
the coupling of aryl or vinyl metal reagents with a meso-
dichloroarene–Cr complex (Csp2–Csp2 coupling) provided
planarly chiral products with a moderate enantioselectivity.5a–c
In the coupling of aryl Grignard reagents with a meso-biaryl
ditriflate (Csp2–Csp2 coupling), axially chiral biaryl compounds
were obtained in a highly enantioselective manner.5d,e The
enantioselective coupling of aryl metal reagents with aryl
halides (Csp2–Csp2 coupling), which induces axial chirality, is
another successful example.6 The asymmetric Buchwald–
Hartwig amination has also been reported, in which the
coupling of amides with aryl halides (Nsp3–Csp2 coupling) gave
axially chiral anilides with a high ee.7 Recently, Ni-catalyzed
enantioselective couplings of alkyl metal reagents with
secondary electrophiles, such as allylic halides, benzyl halides
and a-bromoesters (Csp3–Csp3 coupling), have also been
reported.8 However, it is difficult to induce a new chiral motif
in Csp–Csp2 couplings because of the rigid and linear alkynyl
moiety,9 and asymmetric Sonogashira couplings have never
previously been reported.
shown in Fig. 1; when the ansa chain of a dihaloparacyclo-
phane is sufficiently long, interconversion between its
enantiomers readily occurs, even at room temperature. In
the doubly-alkynylated product, however, planar chirality
must be generated, because the rigid and linear alkynyl
moieties serve as ‘‘props’’, which prevent interconversion from
occurring. This can be categorized as a new type of dynamic
kinetic resolution.10
1
We synthesized [6.6]paracyclophane 1a, and the H-NMR
spectrum of its benzylic methylene protons (dashed circles in
Fig. 2) gave a multiplet (left spectrum). This suggests that the
two enantiomers of the cyclophane do not freely interconvert,
and they were observed by HPLC analysis using a chiral
1
column.11 In contrast, the H-NMR spectrum of the corres-
ponding protons of [7.7]paracyclophane 1b gave a broad
signal (Fig. 2, right spectrum) and, HPLC analysis under the
same conditions showed a single peak.12 Based on these
results, we assumed that the enantiomers of paracyclophane
1b can freely interconvert at room temperature and submitted
it to asymmetric Sonogashira coupling.
We chose p-ethynylanisole as a model alkyne and examined
its double coupling with 1b under the reaction conditions of
Sonogashira coupling (PdCl2(CH3CN)2, CuI and Cs2CO3 as a
base13), using (R)-BINAP as a chiral ligand. The doubly-
alkynylated product, 2ba, was obtained in an excellent yield
with a moderate ee of 29% (Table 1, entry 1).14 When
(S)-BINAP was used, the opposite enantiomer was the major
This Communication demonstrates the first example of an
asymmetric Sonogashira coupling (Csp–Csp2 coupling) in the
enantioselective synthesis of chiral paracyclophanes. Our
concept for the asymmetric induction of planar chirality is
Department of Chemistry and Biochemistry, School of Advanced
Science and Engineering, Waseda University, Shinjuku, Tokyo,
169-8555, Japan. E-mail: tshibata@waseda.jp;
Fax: +81 3-5286-8098; Tel: +81 3-5286-8098
w Electronic supplementary information (ESI) available: Experimental
details and characterization data. See DOI: 10.1039/b818904h
1
Fig. 2 The H-NMR spectra of paracyclophanes 1a and 1b.
ꢀc
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Table 1 Screening of chiral ligands for the asymmetric Sonogashira
coupling of cyclophane 1b
Table 2 The asymmetric Sonogashira coupling of cyclophane 1b with
various alkynes
Entry
R
Time/h
Yield (%) ee (%)
1
2
3
Phenyl
18
12
24
48
18
51
72
72
40
18
72
72
96
87 (2bb)
91 (2ba)
92 (2bc)
92 (2bd)
90 (2be)
90 (2bf)
81 (2bg)
85 (2bh)
71 (2bi)
99 (2bj)
71 (2bk)
73 (2bl)
87 (2bm)
56
52
59
69
62
61
56
72
77
66
72
79
78
Entry
Ligand
Time/h
Yield (%) ee (%)
p-Methoxyphenyl
m-Methoxyphenyl
o-Methoxyphenyl
o-Methylphenyl
2-Biphenyl
o-Chlorophenyl
o-Bromophenyl
o-Acetylphenyl
2,6-Dimethoxyphenyl
2,6-Dibromophenyl
CH2OMe
1
2
3
4
5
6
7
8
9
(R)-BINAP
(S)-BINAP
(S)-tol-BINAP
(S)-H8-BINAP
(S)-SEGPHOSa
(R)-(S)-PPFA
(R)-(S)-Josiphos
(R)-(R)-Walphos
(R)-(S)-Mandyphos
(R)-(R)-Taniaphos 1
(R)-(R)-Taniaphos 2
(R)-(R)-Taniaphos 3
18
15
27
9
10
6
24
48
6
99
95
98
98
88
93
33
33
85
98
66
91
29
ꢁ35
5
ꢁ14
ꢁ4
o2
ꢁ7
6
4
5a
6
7
8
9
10
11
12
13
ꢁ26
10
11
12
6
18
6
57
34
CH2OBn
44
a
6 equiv. of alkyne were used.
a
SEGPHOS: 5,50-bis(diphenylphosphino)-4,40-bi-1,3-benzodioxole.
Table 3 The asymmetric Sonogashira coupling of cyclophanes with
different ansa chains
product (Table 1, entry 2), which meant that our concept of
the enantioselective generation of planar chirality had been
realized. BINAP derivatives also achieved high to excellent
yields, but the enantioselectivities were low (Table 1, entries 3–5).
In the case of PPFA, the enantioselectivity was low, but
the reaction was concluded within a shorter time (Table 1,
entry 6). Thus, we examined other ferrocene-based ligands:
Josiphos and Walphos gave poor results in terms of both
yield and enantioselectivity (Table 1, entries 7 and 8), and
Mandyphos gave a good yield, although the enantioselectivity
was not improved (Table 1, entry 9). Taniaphos 1 achieved the
best enantioselectivity, with an excellent yield (Table 1, entry 10).
After screening Taniaphos derivatives (Table 1, entries 11 and 12),
we chose Taniaphos 1 for further investigations.
Entry
1
Z
Time/h Yield (%) ee (%)
48
81 (2cm)
78
(1c)
We used 10 mol% of chiral Pd catalyst and screened various
alkynes in the asymmetric Sonogashira couplings with 1b
(Table 2). The coupling with phenylacetylene gave dialkynyl-
ated product 2bb in a 56% ee (Table 2, entry 1). In the case of
o-ethynylanisole, a higher enantioselectivity was achieved
than with m- or p-ethynylanisole (Table 2, entries 2–4). The
coupling of 1b with various ortho-substituted ethynylbenzenes
was examined (Table 2, entries 5–9), and the enantio-
selectivities were more than 70% when 1-bromo-2-ethynyl-
benzene and 1-acetyl-2-ethynylbenzene were used (Table 2,
2
3
54
48
91 (2dm)
89 (2em)
73
77
(1d)
(1e)
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entries 8 and 9). The enantioselectivity of a 2,6-disubsutituted
ethynylbenzene was comparable to that of a 2-monosubstituted
example (Table 2, entries 10 and 11). Furthermore, the
coupling of 1b with propargyl ethers achieved the best
enantioselectivity of ca. 80% (Table 2, entries 12 and 13).
Next, we examined the coupling of other paracyclophanes
with benzyl propargyl ether (Table 3). Hexaoxa[7.7]paracyclo-
phane 1c, which has six oxygen atoms on its ansa chain
(Table 3, entry 1), [7](1,4)naphthaleno[7]paracyclophane 1d
(Table 3, entry 2) and [18]paracyclophane 1e with an aliphatic
ansa chain (Table 3, entry 3), were examined. The correspond-
ing dialkynylated products were obtained in good to high
yields, with enantioselectivities as good as those of 1b.
Y. Uozumi, J. Am. Chem. Soc., 1995, 117, 9101;
(e) T. Kamikawa, Y. Uozumi and T. Hayashi, Tetrahedron Lett.,
1996, 37, 3161.
6 For asymmetric Kumada couplings, see: (a) K. Tamao, A. Minato,
N. Miyake, T. Matsuda, Y. Kiso and M. Kumada, Chem. Lett.,
1975, 133; (b) K. Tamao, H. Yamamoto, H. Matsumoto,
N. Miyake, T. Hayashi and M. Kumada, Tetrahedron Lett.,
1977, 18, 1389; (c) T. Hayashi, K. Hayashizaki, T. Kiyoi and
Y. Ito, J. Am. Chem. Soc., 1988, 110, 8153; (d) T. Hayashi,
K. Hayashizaki and Y. Ito, Tetrahedron Lett., 1989, 30, 215. For
asymmetric Suzuki couplings, see: (e) A. N. Cammidge and K. V.
L. Crepy, Chem. Commun., 2000, 1723; (f) J. Yin and
´
S. L. Buchwald, J. Am. Chem. Soc., 2000, 122, 12051;
(g) A.-S. Castanet, F. Colobert, P.-E. Broutin and M. Obringer,
Tetrahedron: Asymmetry, 2002, 13, 659; (h) A. Herrbach,
A. Marinetti, O. Baudoin, D. Gue
Chem., 2003, 68, 4897; (i) A. N. Cammidge and K. V. L. Cre
Tetrahedron, 2004, 60, 4377; (j) M. Genov, A. Almorın and
´
nard and F. Gue
´
ritte, J. Org.
´
py,
In conclusion, we have developed an asymmetric
Sonogashira coupling of diiodoparacyclophanes to give
planarly chiral dialkynylparacyclophanes with ca. 80% ee.
The present results are also notable from a synthetic point
of view, because planarly chiral paracyclophanes are useful
chiral motifs and functional materials;15 PHANEPHOS
derivatives as chiral ligands16 and parapyridinophane
derivatives as co-enzyme models17 are the selected examples.
However, there has been only one report of enantioselective
and catalytic syntheses of chiral paracyclophanes.18 Therefore,
we have demonstrated the enantioselective synthesis of chiral
paracyclophanes based on the new concept of asymmetric
induction, and its use in other reactions is under investigation.
K. K. gives thanks for a Grant-in-Aid from the Japan
Society for the Promotion of Science (JSPS) Fellows. We also
thank Solvias for the gift of asymmetric ligand screening kits.
´
P. Espinet, Chem.–Eur. J., 2006, 12, 9346. For asymmetric Negishi
couplings, see: (k) M. Genov, B. Fuentes, P. Espinet and B. Pelaz,
Tetrahedron: Asymmetry, 2006, 17, 2593. For microwave-assisted
asymmetric Suzuki and Negishi couplings, see: (l) M. Genov,
´
A. Almorın and P. Espinet, Tetrahedron: Asymmetry, 2007, 18,
625.
7 (a) O. Kitagawa, M. Kohriyama and T. Taguchi, J. Org. Chem.,
2002, 67, 8682; (b) J. Terauchi and D. P. Curran, Tetrahedron:
Asymmetry, 2003, 14, 587; (c) O. Kitagawa, M. Takahashi,
M. Yoshikawa and T. Taguchi, J. Am. Chem. Soc., 2005, 127,
3676; (d) O. Kitagawa, M. Yoshikawa, H. Tanabe, T. Morita,
M. Takahashi, Y. Dobashi and T. Taguchi, J. Am. Chem. Soc.,
2006, 128, 12923.
8 (a) C. Fischer and G. C. Fu, J. Am. Chem. Soc., 2005, 127, 4594;
(b) F. O. Arp and G. C. Fu, J. Am. Chem. Soc., 2005, 127, 10482;
(c) S. Son and G. C. Fu, J. Am. Chem. Soc., 2008, 130, 2756;
(d) X. Dai, N. A. Strotman and G. C. Fu, J. Am. Chem. Soc., 2008,
130, 3302; (e) B. Saito and G. C. Fu, J. Am. Chem. Soc., 2008, 130,
6694. The enantioselective Ni-catalyzed cross coupling of
secondary benzyl bromides with trialkynylindium (Csp3–Csp
coupling) has also been reported; see: (f) J. Caeiro, J. P. Sestelo
and L. A. Sarandeses, Chem.–Eur. J., 2008, 14, 741.
9 Only one example of asymmetric Csp–Csp2 coupling has been
reported: the enantioposition-selective coupling of a meso-biaryl
ditriflate with an alkynyl Grignard reagent gave axially chiral
biaryl compounds; see ref. 5e.
Notes and references
1 (a) Handbook of Organopalladium Chemistry for Organic Synthesis,
ed. E. Negishi and A. De Meijere, Wiley-Interscience, New York,
USA, 2002; (b) J. Tsuji, Palladium Reagents and Catalysts: New
Perspectives for the 21st Century, Wiley, Chichester, UK, 2004;
(c) J. Tsuji, Palladium in Organic Synthesis, Springer, Berlin,
Germany, 2005.
10 For reviews of dynamic kinetic resolution, see: (a) F. F. Huerta,
A. B. E. Minidis and J.-E. Backvall, Chem. Soc. Rev., 2001, 30,
¨
2 K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem., Int.
Ed., 2005, 44, 4442.
321; (b) H. Pellissier, Tetrahedron, 2003, 59, 8291; (c) H. Pellissier,
Tetrahedron, 2008, 64, 1563.
3 For reviews, see: (a) T. Hayashi, in Comprehensive Asymmetric
Catalysis, ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto,
Springer, Berlin, Germany, 1999, vol. 2, pp. 888;
(b) M. Ogasawara and T. Hayashi, in Catalytic Asymmetric
Synthesis, ed. I. Ojima, Wiley-VCH, New York, USA, 2000,
pp. 651; (c) T. Hayashi, J. Organomet. Chem., 2002, 653, 41.
4 (a) G. Consiglio and C. Botteghi, Helv. Chim. Acta, 1973, 56, 460;
(b) Y. Kiso, K. Tamao, N. Miyake, K. Yamamoto and
M. Kumada, Tetrahedron Lett., 1974, 15, 3; (c) T. Hayashi,
M. Tajika, K. Tamao and M. Kumada, J. Am. Chem. Soc.,
1976, 98, 3718; (d) T. Hayashi, M. Fukushima, M. Konishi and
M. Kumada, Tetrahedron Lett., 1980, 21, 79; (e) T. Hayashi,
M. Konishi, M. Fukushima, T. Mise, M. Kagotani, M. Tajika
and M. Kumada, J. Am. Chem. Soc., 1982, 104, 180;
(f) T. Hayashi, M. Konishi, H. Ito and M. Kumada, J. Am. Chem.
Soc., 1982, 104, 4962; (g) T. Hayashi, M. Konishi, M. Fukushima,
K. Kanehira, T. Hioki and M. Kumada, J. Org. Chem., 1983, 48,
2195; (h) T. Hayashi, T. Hagihara, Y. Katsuro and M. Kumada,
Bull. Chem. Soc. Jpn., 1983, 56, 363; (i) T. Hayashi, M. Konishi,
Y. Okamoto, K. Kabeta and M. Kumada, J. Org. Chem., 1986, 51,
3772; (j) T. Hayashi, A. Yamamoto, M. Hojo and Y. Ito, J. Chem.
Soc., Chem. Commun., 1989, 495.
11 Daicel Chiralpak IA: 4 ꢂ 250 mm, 254 nm UV detector, rt; eluent:
20% CH2Cl2 in hexane, flow rate: 1.0 mL minꢁ1
.
12 As far as we investigated (Chiralpak IA, IB, AD, and Chiralcel
OD, OJ), the HPLC analyses of compound 1b showed a single
peak.
13 The choice of base is very important: when triethylamine was used,
the reaction proceeded sluggishly and the yield of dialkynylated
product 2ba was moderate (43%), along with the formation of
monoalkynylated product (40%).
14 The 1H-NMR spectrum of the benzylic methylene protons of 2ba
was a multiplet, and the enantiomers were observed by HPLC
analysis using a chiral column (Daicel Chiralpak IA: 4 ꢂ 250 mm,
254 nm UV detector, rt; eluent: 30% CH2Cl2 in hexane, flow rate:
1.0 mL minꢁ1).
15 For reviews of cyclophanes, see: (a) Cyclophane Chemistry,
ed. F. Vogtle, Wiley, Chichester, UK, 1993; (b) Modern Cyclophane
¨
Chemistry, ed. R. Gleither and H. Hopf, Wiley, Chichester, UK,
2004.
16 P. J. Pye, K. Rossen, R. A. Reamer, N. N. Tsou, R. P. Volante and
P. J. Reider, J. Am. Chem. Soc., 1997, 119, 6207.
17 (a) N. Kanomata and T. Nakata, Angew. Chem., Int. Ed. Engl.,
1997, 36, 1207; (b) N. Kanomata and T. Nakata, J. Am. Chem.
Soc., 2000, 122, 4563.
18 A chiral Rh complex catalyzed the coupling of 1,4-bis(bromo-
methyl)benzene derivatives with dithiols to give chiral dithiapara-
cyclophanes (up to 60% ee): K. Tanaka, T. Hori, T. Osaka,
K. Noguchi and M. Hirano, Org. Lett., 2007, 9, 4881.
5 (a) M. Uemura, H. Nishimura and T. Hayashi, Tetrahedron Lett.,
1993, 34, 107; (b) M. Uemura, H. Nishimura and T. Hayashi,
J. Organomet. Chem., 1994, 473, 129; (c) K. Kamikawa, K. Harada
and M. Uemura, Tetrahedron: Asymmetry, 2005, 16, 1419;
(d) T. Hayashi, S. Niizuma, T. Kamikawa, N. Suzuki and
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This journal is The Royal Society of Chemistry 2009
1872 | Chem. Commun., 2009, 1870–1872