Palladium(II)-catalyzed asymmetric cycloisomerization of enynes for axially chiral biaryl construction

Article abstract of DOI:10.1016/j.tetlet.2012.11.071

Palladium(II)-catalyzed asymmetric cycloisomerization of enynes with (R)-binap gave axially chiral biaryls with up to 99%ee. The reactivity and enantioselectivity depended on the nature and position of substituent of the arene ring. The enynes with ortho methoxy arene at alkyne terminus gave chiral biaryls with good enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2012.11.071

Tetrahedron Letters 54 (2013) 512–514
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium(II)-catalyzed asymmetric cycloisomerization of enynes for axially
chiral biaryl construction
⇑
Nobuaki Kadoya, Masato Murai, Masako Ishiguro, Jun’ichi Uenishi, Motokazu Uemura
Kyoto Pharmaceutical University, Kyoto 607-8412, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium(II)-catalyzed asymmetric cycloisomerization of enynes with (R)-binap gave axially chiral biar-
yls with up to 99%ee. The reactivity and enantioselectivity depended on the nature and position of sub-
stituent of the arene ring. The enynes with ortho methoxy arene at alkyne terminus gave chiral biaryls
with good enantioselectivity.
Received 1 October 2012
Revised 15 November 2012
Accepted 19 November 2012
Available online 24 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Axially chiral biaryl
Asymmetric cycloisomerization
Enyne compounds
Palladium catalyst
Axially chiral biaryls are valuable compounds as chiral ligands
or auxiliaries in asymmetric reaction, and also for biologically ac-
tive natural products. There is a considerable current interest in
the development of efficient methodologies for the synthesis of
axially chiral biaryls.1 Catalytic asymmetric synthesis of the axially
chiral biaryls has been dramatically increased. Asymmetric biaryl
coupling such as Suzuki,2 Kumada,3 and Negishi4 coupling is
achieved with high enantioselectivity in some cases. Asymmetric
aromatization through transition-metal catalyzed [2+2+2]-cyc-
loadditions of dienynes with alkynes or nitriles has also been a
powerful method for axially chiral biaryl construction. For this pur-
pose, Co(I),5 Ir(I),6 and Rh(I)7 complexes with chiral ligands have
been utilized for asymmetric cycloadditions. On the other hand,
metal-catalyzed cycloisomerization of enyne compounds leading
to carbocycles and heterocycles has been actively investigated.
(o-Alkynyl)styrenes afforded functionalized naphthalenes via the
6-endo reaction pathway with gold(I) catalyst in good yields.8 We
previously reported that achiral gold(I)-catalyzed cycloisomeriza-
tion of the planar chiral alkynyl arene chromium complexes bear-
ing a styrene unit afforded diastereoselectively axially chiral biaryl
chromium complexes, which were converted into chromium-free
axial biaryls by demetallation.9 Although the axially chiral biaryls
could be obtained with high optical purity in this methodology, a
most problematic limitation is access to the enantiomerically pure
(arylhalide)Cr(CO)3 complex as a starting material.10 And, this pro-
cedure is a diastereoselective reaction utilizing the planar chiral
arene chromium complex. Herein, we would like to report an
asymmetric version of metal-catalyzed cycloisomerization of the
corresponding chromium-free enyne compounds for axially chiral
biaryls.
Initial efforts have focused on the optimization of an efficient
system of the metal-catalyzed asymmetric reaction starting from
1-((2-cyclopentenylphenyl)ethynyl)-2-methoxynaphthalene
(1)
as a model substrate (Table 1). Among the surveys of a variety of
metal catalysts,11,12 cationic Au(I) catalysts showed a high catalytic
activity for the cycloisomerization of enyne 1 at room temperature
giving axially chiral biaryl compound 2 in good yield, but the
enantioselectivity of 2 was only 15%ee (entry 1). A combination
of chloro(1,5-cyclooctadiene)rhodium(I) dimer with AgSbF6 gave
no cycloisomerization product (entry 2). An isolated cationic
rhodium catalyst at 60 °C was also ineffective (entry 3). Moreover,
palladium(0) and palladium(II) acetate resulted in no cycloisomer-
ization reaction (entries 4, 5). Fortunately, tetrakis(acetonitrile)-
palladium(II) tetrafluoroborate in the presence of (R)-binap at
80 °C in 1,2-dichloroethane afforded the axially chiral biaryl 2 in
90% yield with 53%ee (entry 6).
This cationic Pd(II) catalyst is more Lewis acidic and can enhance
the coordinating ability with the triple bond. Although the related
N-alkenyl arylethynylamides were smoothly converted into chiral
aryl 2-pyridone derivatives at room temperature by metal-cata-
lyzed cycloisomerization,13 the enyne compound 1 is required to
heat for the cyclization. As the central bond rotation of the biaryl
compound 2 would occur under the thermal conditions, we next
examined an optimum reaction temperature for the achievement
of higher ee value. The enantioselectivity of the cycloisomerization
product 2 increased to 84%ee at 60 °C, although the chemical yield
decreased to 52% (entry 7). At 50 °C, the enantiomeric excess was
⇑
Corresponding author. Tel.: +81 75 595 4666; fax: +81 75 595 4763.
E-mail address: muemura@mb.kyoto-phu.ac.jp (M. Uemura).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.071

N. Kadoya et al. / Tetrahedron Letters 54 (2013) 512–514
513
Table 1
Table 2
Screening of asymmetric cycloisomerization
Cationic palladium(I)-catalyzed asymmetric cycloisomerization of enyne compounds
with (R)-binapa
Entry
Enyne compound
R2
Product
Yield (%ee)
ML*
R2
R3
(*)
OMe
ClCH2CH2Cl
(
)
*
OMe
6h
R3
R1
1
2
R1
1: R1 = OMe, R2 = R3 = H
3: R1 = R2 = OMe, R3 = H
5: R1 = R3 = OMe, R2 = H
7: R1 = Me, R2 = R3 = H
2
4
6
8
10
12
52 (84)
88 (82)
90 (49)
0 (ꢀ)
Entry
ML⁄
Temp (°C)
Yield (%ee)
1
2
3
4
5
6
1a
2
3
4
5
[Au2(R)-binap]Cl2], AgNTf2
[Rh(COD)Cl]2, AgSbF6, (R)-binap
[Rh(COD)(R)-binap](BF4)
Pd2(dba)3, (R)-binap
Pd(OCOCF3)2, (R)-binap
[Pd(MeCN)4](BF4)2, (R)-binap
[Pd(MeCN)4](BF4)2, (R)-binap
[Pd(MeCN)4](BF4)2, (R)-binap
[Pd(MeCN)4](BF4)2, (R)-xylylbinap
[Pd(MeCN)4](BF4)2, (R)-segphos
[Pd(MeCN)4](BF4)2, (R)-tolbinap
[Pd(MeCN)4](BF4)2, (R)-H8-binap
Rt
Rt
95 (15)
0 (ꢀ)
60
80
80
80
60
50
60
60
60
60
0 (ꢀ)
9: R1 = Me, R2 = OMe, R3 = H
11: R1 = Me, R2 = H, R3 = OMe
69 (0)
0 (ꢀ)
0 (ꢀ)
0 (ꢀ)
6b
7b
8b
9b
10b
11b
12b
90 (53)
52 (84)
50 (84)
10 (54)
8 (73)
17 (81)
41 (70)
OMe
OMe
MeO
MeO
( )
*
a
R
The reaction was performed using 5 mol % of gold catalyst and 10 mol % of Ag
salt in CH2Cl2.
R
13: R = OMe
15: R = Me
7
8
14
16
66 (59)
86 (53)
b
The reaction condition is 5 mol % of palladium catalyst and 6–10 mol % of chiral
ligand.
R
R
Me
nearly equal to that of the conditions at 60 °C. This fact indicates
that no central bond rotation of the axially chiral biaryl 2 takes
place under the reaction conditions of lower temperature than
60 °C. With other chiral ligands, any advantages concerning both
the yield and enantiomeric excess of compound 2 were not ob-
served (entries 9–13).
Me
( )
*
OMe
OMe
17: R = H
19: R = OMe
9b
18
20
65 (99)
77 (83)
10b
Under these optimized conditions using [Pd(MeCN)4](BF4)2 cat-
alyst and (R)-binap, we next explored the scope of the asymmetric
cycloisomerization with a modification of the substituent on the
arene rings (Table 2). 2-Methylnaphthyl substituted enyne com-
pound 7 gave no cycloisomerization product 8 under these condi-
tions (entry 4). We anticipated that the enyne compounds
possessing an electron rich arene or alkene should be required
for the achievement of cycloisomerization. Therefore, an elec-
tron-donating MeO group was introduced on the phenyl ring for
an enhancement of the electron-density. 2-Cyclopentenyl-3-
methoxyphenyl substituted enyne compound 9 gave expectedly
cycloisomerization product 10 in good yield, albeit the product
was racemic (entry 5). For the asymmetric induction in the palla-
dium-catalyzed cycloisomerization, the methoxy group at the
neighboring position of the triple bond is an important factor.13
A coordination structure of the cationic palladium(II) metal with
methoxy group would induce a rigid environment in the asymmet-
ric cycloisomerization. But, the regioisomeric 6-methoxyphenyl
substituted enyne compound 11 afforded no cyclization product
(entry 6). Lower ee value in entry 3 compared with the value of en-
try 2 would have contributed to form two different coordination
intermediates of the palladium with methoxy group in compound
5. Next, the asymmetric cycloisomerization of electron-rich arene
substituted alkynes as a nucleophile was examined. 30,50-Dim-
ethoxylbiphenyl substituted alkynes 13 and 15 gave cycloisomer-
ization products 14 and 16, respectively, with modest to good
enantiomeric excesses (entries 7, 8). With 1-methoxy-3-methyl-
phenyl substituted enyne compounds 17, 19, and 23, the cycloiso-
merization products 18, 20, and 24 were obtained with higher
enantiomeric excess values than 2-methoxynaphthyl substituted
enyne analogs (entries 9, 12, 13). Particularly, 2-((2-cyclopentenyl-
phenyl)ethynyl)-1-methoxy-3-methylbenzene (17) gave an excellent
( )
*
OMe
OMe
11
21
22
49 (79)
Me
Me
(
)
*
OMe
Me
)
OMe
12b
23
24
71 (95)
Me
Me
Me
Me
Me
(
*
OMe
OMe
13
25
26
75 (87)
Me
Me
Me
Me
Me
Me
(
)
*
OMe
OMe
14
27
26
47 (62)
a
Reactions were performed using [Pd(MeCN)4](BF4)2 (5 mol %) and (R)-binap
(10 mol %) in (CH2Cl)2 at 60 °C for 6 h.
b
Reaction temperature 50 °C, reaction time 24 h.

514
N. Kadoya et al. / Tetrahedron Letters 54 (2013) 512–514
Lu, B. Z.; Yee, N. K.; Senanayake, C. H. Org. Lett. 2012, 14, 2258–2261; (h) Zhang,
S.-S.; Wang, Z. Q.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2010, 12, 5546–5549; (i)
Genov, M.; Almorín, A.; Espinet, P. Chem. Eur. J. 2006, 12, 9346–9352; (j)
Cammidge, A. N.; Crépy, K. V. L. Chem. Commun. 2000, 1723–1724.
3. For selected references: (a) Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am.
Chem. Soc. 1988, 110, 8153–8156; (b) Hayashi, T.; Niizuma, S.; Kamikawa, T.;
Suzuki, N.; Uozumi, Y. J. Am. Chem. Soc. 1995, 117, 9101–9102; (c) Cammidge, A.
N.; Crépy, K. V. L. Tetrahedron 2004, 60, 4377–4386.
4. Genov, M.; Fuentes, B.; Espinet, P.; Pelaz, B. Tetrahedron: Asymmetry 2006, 17,
2593–2595.
5. Gutnov, A.; Heller, B.; Fischer, C.; Drexler, H.-J.; Spannenberg, A.; Sundermann,
B.; Sundermann, C. Angew. Chem., Int. Ed. 2004, 43, 3795–3797.
6. Shibata, T.; Fujimoto, T.; Yokota, K.; Takagi, K. J. Am. Chem. Soc. 2004, 126,
8382–8383.
7. A review and selected references: (a) Tanaka, K. Synlett 2007, 1977–1997; (b)
Tanaka, K.; Nishida, G.; Wada, A.; Noguchi, K. Angew. Chem., Int. Ed. 2004, 43,
6510–6512; (c) Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2005, 7, 4737–4739;
(d) Oppenheimer, J.; Johnson, W. L.; Figueroa, R.; Hayashi, R.; Hsung, R. P.
Tetrahedron 2009, 65, 5001–5012; (e) Mori, F.; Fukawa, N.; Noguchi, K.; Tanaka,
K. Org. Lett. 2011, 13, 362–365.
8. (a) Fürstner, A.; Mamane, V. J. Org. Chem. 2002, 67, 6264–6267; (b) Fürstner, A.;
Kennedy, J. W. J. Chem. Eur. J. 2006, 12, 7398–7410; (c) Shibata, T.; Ueno, Y.;
Kanda, K. Synlett 2006, 411–414; (d) Dankwardt, J. W. Tetrahedron Lett. 2001,
42, 5809–5812; (e) Lin, M.-Y.; Das, A.; Liu, R.-S. J. Am. Chem. Soc. 2006, 128,
9340–9341.
Me
Me
PPh3AuNTf2
CH2Cl2
hν, air
(+)-18
OMe
OMe
Cr(CO)3
Cr(CO)3
29
[α]D20 +99 (c 0.25, CHCl3)
28
[α]D20 +209.4 (c 0.50, CHCl3)
Scheme 1. Absolute configuration.
enantioselectivity at 50 °C (entry 9). Similarly, cyclohexenyl
substituted enyne compounds gave the corresponding axially chi-
ral biaryls in good yield with high enantioselectivity. With acyclic
substituted enyne compounds, the geometry of the double bond
affects significantly the reactivity and enantioselectivity as follows.
E-Configurated enyne 25 gave axially chiral biaryl 26 in 75% yield
with 86%ee (entry 13), while the corresponding Z-isomer 27 re-
sulted in lower yield and enantioselectivity due to steric hindrance
(entry 14). Both major enantiomers are of identical absolute con-
figuration regardless of the geometry of starting material.
The absolute configuration of biaryl compound 18 obtained by
the use of palladium/(R)-binap was determined as (S)-configura-
tion by a comparison with the authentic compound (Scheme 1).
Planar chiral enyne chromium complex (+)-2814 was treated with
PPh3AuNTf2 to give diastereoselectively anti-biaryl chromium
complex9 (+)-29. The stereochemistry of 29 was confirmed by
X-ray crystallography.15 A photo-oxidative demetallation of 29
afforded chromium-free axially chiral biaryl compound (+)-18
which was identical with palladium-catalyzed cycloisomerization
product 18 by chiral HPLC analysis.
9. (a) Michon, C.; Liu, S.; Hiragushi, S.; Uenishi, J.; Uemura, M. Tetrahedron 2008,
64, 11756–11762; (b) Michon, C.; Liu, S.; Hiragushi, S.; Uenishi, J.; Uemura, M.
Synlett 2008, 1321–1324.
10. Uemura, M. In Org. React.; Wiley: New Jersey, 2006; Vol. 67, p. 217.
11. For
a selected review of metal-catalyzed cycloisomerization of enyne
compounds: (a) Michelet, V.; Toullec, P. Y.; Genét, J.-P. Angew. Chem., Int. Ed.
2008, 47, 4268–4315; Asymmetric version: (b) Fairlamb, I. J. S. Angew. Chem.,
Int. Ed. 2004, 43, 1048–1052; (c) Watson, I. D. G.; Toste, F. D. Chem. Sci. 2012, 3,
2899–2929.
12. For selected examples of transition metal complex catalyzed asymmetric
cycloisomerization of enyne compounds. Au(I) catalyst: (a) Martínez, A.;
García-García, P.; Fernández-Rodríguez, M. A.; Rodríguez, F.; Sanz, R. Angew.
Chem., Int. Ed. 2010, 49, 4633–4637; (b) Munoz, M. P.; Adrio, J.; Carretero, J. C.;
Echavarren, A. M. Organometallics 2005, 24, 1293–1300; (c) Chao, C.-M.; Vitale,
M. R.; Toullec, P. Y.; Genét, J.-P.; Michelet, V. Chem. Eur. J. 2009, 15, 1319–1323;
Palladium catalyst: (d) Trost, B. M.; Czeskis, B. A. Tetrahedron Lett. 1994, 35,
211–214; (e) Trost, B. M.; Lee, D. C.; Rise, F. Tetrahedron Lett. 1989, 30, 651–
654; (f) Goeke, A.; Sawamura, M.; Kuwano, R.; Ito, Y. Angew. Chem., Int. Ed. Engl.
1996, 35, 662–663; (g) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2007, 129,
2764–2765; (h) Hatano, M.; Mikami, K. J. Am. Chem. Soc. 2003, 125, 4704–4705;
(i) Hatano, M.; Terada, M.; Mikami, K. Angew. Chem., Int. Ed. 2001, 40, 249–253;
Rh catalyst: (j) Lei, A.; Waldkirch, J. P.; He, M.; Zhang, X. Angew. Chem., Int. Ed.
2002, 41, 4526–4529; (k) Lei, A.; He, M.; Wu, S.; Zhang, X. Angew. Chem., Int. Ed.
2002, 41, 3457–3460; (l) Lei, A.; Ne, M.; Zhang, X. J. Am. Chem. Soc. 2002, 124,
8198–8199; (m) Chakrapani, H.; Liu, C.; Wiedenhoefer, R. A. Org. Lett. 2003, 5,
157–159; (n) Porcel, S.; Echavarren, A. M. Angew. Chem., Int. Ed. 2007, 46, 2672–
2676.
In conclusion, the palladium-catalyzed asymmetric cycloiso-
merization of enynes with (R)-binap gave the axially chiral biaryls
in good yields with moderate to good enantioselectivity.16
Acknowledgments
13. (a) Shibuya, T.; Shibata, Y.; Noguchi, K.; Tanaka, K. Angew. Chem., Int. Ed. 2011,
50, 3963–3967; (b) Imase, H.; Suda, T.; Shibata, Y.; Noguchi, K.; Hirano, M.;
Tanaka, K. Org. Lett. 2009, 11, 1805–1808.
14. Planar chiral enyne chromium complex 28 was prepared from enantiomeri-
cally pure (+)-tricarbonyl(2-methoxy-6-methyl-1-bromobenzene)chromium
by Sonogashira coupling with trimethylsilylacetylene followed by desily-
lation and further coupling with 1-cyclopentenyl-2-iodobenzene (see;
Supplementary data).
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
Supplementary data
15. Crysatallographic data of compound 29 (CCDC 895657).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.11.
071.
16. Typical procedure of palladium-catalyzed asymmetric cycloisomerization; A
mixture of [Pd(MeCN)4](BF4)2 (2.30 mg, 5 mol %) and (R)-binap (6.90 mg,
10 mol %) in 1,2-dichloroethane (4 mL) was stirred at room temperature for
10 min under argon atmosphere. To the reaction mixture, a solution of 2-((2-
cyclopentenylphenyl)ethynyl)-1-methoxy-3-methylbenzene (17) (30.4 mg,
References and notes
0.105 mmol) in 1,2-dichloroethane (0.5 mL) was added by
a syringe. The
reaction mixture was heated at 50 °C for 24 h under argon, and cooled to room
temperature. The mixture was diluted with ether and filtered through celite.
The organic layer was evaporated under reduced pressure and the residue was
purified by silica gel column chromatography with ether and hexane (1:20) to
give 19.7 mg (65%) of 2-methoxy-6-methyl-1-{benzo((b)[2,3-dihydro-1H-
1. For selected reviews: (a) Wallace, T. W. Org. Biomol. Chem. 2006, 4, 3197–3210;
(b) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.; Garner, J.;
Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384–5427; (c) Kozlowsky, M. C.;
Morgan, B. J.; Linton, E. C. Chem. Soc. Rev. 2009, 38, 3193–3207; (d) Bringmann,
G.; Gulder, T.; Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem. Rev. 2011, 111,
563–639.
2. For recent selected references: (a) Bermejo, A.; Ros, A.; Fernández, R.;
Lassaletta, J. M. J. Am. Chem. Soc. 2008, 130, 15798–15799; (b) Sawai, K.;
Tatsumi, R.; Nakahodo, T.; Fujihara, H. Angew. Chem., Int. Ed. 2008, 47, 6917–
6919; (c) Uozumi, Y.; Matsuura, Y.; Arakawa, T.; Yamada, Y. M. A. Angew. Chem.,
Int. Ed. 2009, 48, 2708–2710; (d) Shen, X.; Jones, G. O.; Watson, D. A.; Bhayana,
B.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 11278–11287; (e) Yamamoto, T.;
Akai, Y.; Nagata, Y.; Suginome, M. Angew. Chem., Int. Ed. 2011, 50, 8844–8847;
(g) Tang, W.; Patel, N. D.; Xu, G.; Xu, X.; Savoie, J.; Ma, S.; Hao, M.-H.;
Keshipeddy, S.; Capacci, A. G.; Wei, X.; Zhang, Y.; Gao, J. J.; Li, W.; Rodriguez, S.;
inden-4-yl]benzene (18) as a colorless liquid; ½a 2D0 + 5.4° (c 0.10, CHCl3); 1H
ꢁ
NMR (400 MHz, CDCl3) d 7.83 (1H, d, J = 7.6 Hz), 7.82 (1H, d, J = 8.0 Hz), 7.47
(1H, t, J = 7.6 Hz), 7.48 (1H, s), 7.41 (1H, t, J = 7.6 Hz), 7.25 (1H, d, J = 8.0 Hz),
6.92 (1H, d, J = 7.6 Hz), 6.84 (1H, d, J = 8.0 Hz), 3.69 (3H, s), 3.33 (2H, t,
J = 7.6 Hz), 2.85–2.62 (2H, m), 2.24–2.16 (2H, m), 2.02 (3H, s); 13C NMR
(100 MHz, CDCl3) d 157.2, 141.6, 139.5, 137.9, 133.5, 133.1, 129.93, 129.92,
128.5, 128.1, 127.0, 125.6, 124.8, 124.5, 122.5, 108.3, 55.8, 32.9, 31.7, 24.4,
20.4; HRMS calcd for C21H20O: 288.1514. found 288.1520. HPLC (Chiralpak AD-
H), UV detector 254 nm, 0.25% i-PrOH in hexane, flow rate 0.5 mL/min;
retention time; 11.4 min (minor isomer), 15.7 min (major isomer).