Iridium-catalyzed enantioselective formal [4+2] cycloaddition of biphenylene and alkynes for the construction of axial chirality

Article abstract of DOI:10.1055/s-2008-1032112

Chiral iridium complex catalyzed a formal [4+2] cycloaddition of biphenylene with disubstituted alkynes, which was initiated by carbon-carbon bond cleavage. Axially chiral 9,10-disubstituted phenanthrenes were enantiomerically obtained. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032112

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765
Iridium-Catalyzed Enantioselective Formal [4+2] Cycloaddition of
Biphenylene and Alkynes for the Construction of Axial Chirality
Formal [4+2]
C
a
ycloadditio
k
n
of Bipheny
a
lene and
A
n
lkynes ori Shibata,* Go Nishizawa, Kohei Endo
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku,
Tokyo 169-8555, Japan
E-mail: tshibata@waseda.jp
Received 30 November 2007
Abstract: Chiral iridium complex catalyzed a formal [4+2] cy-
cloaddition of biphenylene with disubstituted alkynes, which was
initiated by carbon–carbon bond cleavage. Axially chiral 9,10-di-
substituted phenanthrenes were enantiomerically obtained.
R1
R2
R1
MLn*
+
Key words: alkynes, asymmetric catalysis, cycloadditions, iridi-
um, rhodium
R2
axially chiral phenanthrene
reductive elimination
In general, a carbon–carbon single bond is inert and intact
in organic reactions. However, carbon–carbon bond
cleavage in strained molecules with small ring systems,
such as cyclopropane and cyclobutane, could be possible.1
Transition-metal complexes facilitate the bond cleavage,
and catalytic and unique synthetic transformations have
been reported, which were initiated by carbon–carbon
bond cleavage (they are named carbon–carbon bond acti-
vation or functionalization).2 Biphenylene, namely diben-
zocyclobutadiene, which has a severely strained 4-
membered ring, underwent carbon–carbon bond cleav-
age: the reaction of biphenylene with transition-metal
complexes,3 including Ni,4 Ir,5 Rh,6 Co,7 Pt,8 Fe,9 and Pd
ones,10 gave dibenzometallacyclopentadienes. However,
it was not utilized in the catalytic organic syntheses until
Jones and a co-worker reported a Rh-catalyzed reaction of
biphenylene with alkynes.11
MLn*
C-C bond activation
alkyne insertion
MLn*
R1
R2
MLn*
dibenzometalla-
cyclopentadiene
Scheme 1 Strategy for the construction of an axial chirality initiated
by carbon–carbon bond activation of biphenylene
ligand; in particular, in the Ir-catalyzed reaction, alkyne
1a was completely consumed within two hours, and mod-
erate yield and enantiomeric excess were achieved (en-
tries 3 and 4). 1,2-Bis(2,5-dimethylphospholano)ethane
(Me-BPE) further improved both yield and enantioselec-
tivity (entry 6), but iridium–1,2-bis(2,5-diphenylphos-
pholano)ethane (Ir–Ph-BPE) catalyst showed almost no
catalytic activity. In the present enantioselective cycload-
dition, Ir complexes generally operated as more efficient
chiral catalysts than Rh ones, and we used Ir–Me-BPE
catalyst for further investigation.
Here we assumed that, if the formal [4+2] cycloaddition
of biphenylene with a monoalkyne with ortho-substituted
aryl group (R1) on its terminus proceeds, an axial chirality
is generated in the substituted phenanthrene as a cycload-
duct (Scheme 1).
We chose 1-(3-methoxyprop-1-ynyl)-2-methylbenzene
(1a) as a model alkyne and examined the reaction with bi-
phenylene using chiral catalysts, which were prepared in
situ from [RhCl(cod)]2 or [IrCl(cod)]2 and chiral diphos-
phine ligands (Table 1).12 When BINAP was used, the re-
action proceeded sluggishly but the desired substituted
phenanthrene 2a was obtained in low yield, and the gen-
eration of axial chirality in the product was ascertained by
the HPLC analysis using a chiral column. However, its
enantiomeric excess was below 5% for both the Rh- and
Ir-catalyzed reactions (entries 1 and 2). 1,2-Bis(2,5-di-
methylphospholano)benzene (Me-DUPHOS) was a better
We next examined various alkynes under the best reaction
conditions, and the results are summarized in Table 2.13
When a methyl group was introduced into the alkyne ter-
minus in place of methoxymethyl one, enantiomeric ex-
cess of corresponding product 2b was significantly
increased (entry 1). The substituents on the ortho position
of the aryl group drastically influenced the enantioselec-
tivity: in the case of the 2-methoxyphenyl group, the enan-
tiomeric excess of cycloadduct 2c was miserable (entry
2);14 in contrast, in the case of 2-trifluoromethylphenyl
group, the enantiomeric excess of cycloadduct 2d exceed-
ed 90% (entry 3).15 From alkyne 1e with a bulkier siloxy
group, corresponding cycloadduct 2e with slightly lower
enantiomeric excess was obtained (entry 4). These results
SYNLETT 2008, No. 5, pp 0765–0768
x
x.
x
x.
2
0
0
8
Advanced online publication: 26.02.2008
DOI: 10.1055/s-2008-1032112; Art ID: Y02307ST
© Georg Thieme Verlag Stuttgart · New York

766
T. Shibata et al.
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mean that the use of polarized alkynes, which have an
electron-donating group at one side and an electron-with-
drawing one at another side, is very important for high
enantioselectivity. Actually, alkyne 1f with methyl and 2-
trifluoromethylphenyl groups realized the best enantiose-
lectivity (entry 5).16 Diaryl-substituted alkynes also react-
ed with biphenylene and corresponding chiral 9,10-
diarylphenanthrenes 2g and 2h were obtained (entries 6
and 7). Also in these cases, alkyne 1g with the electron-
donating methoxy group on the benzene ring surely gave
better results than the electron-withdrawing methoxycar-
bonyl group.
Table 1 Screening of Reaction Conditions Using Various Chiral Rh
or Ir Complexesa
Me
[MCl(cod)]2 + 2 Ligand
Me
(10 mol%)
+
OMe
xylene, 100 °C
OMe
1a
2a
Entry
M
Rh
Ir
Ligandb
Time (h) Yield (%)ee (%)
The methoxy group of cycloadduct 2g was transformed
into a hydroxy, and the absolute configuration was ascer-
tained as its ferrocenyl ester (Figure 1).
1
2
3
4
5
6
7
BINAP
24
10
24
2
23
<5
<5
37
58
47
65
–
BINAP
31
In summary, we developed an Ir-catalyzed enantioselec-
tive formal [4+2] cycloaddition of biphenylene and
alkynes, which gave 9,10-disubstituted phenanthrenes
with an axial chirality. The two substituents on the
alkynes played a pivotal role for asymmetric induction.
We have already published Ir-catalyzed enantioselective
[2+2+2] cycloaddition of alkynes, which induced axially
chirality(ies) along with benzannulation.17 Therefore, the
present reaction is another new approach to the construc-
tion of axial chirality, which is initiated by carbon–carbon
bond cleavage.
Rh
Ir
Me-DUPHOS
Me-DUPHOS
Me-BPE
45
63
Rh
Ir
Ir
24
2
57
Me-BPE
Ph-BPE
65
10
N.R.
a Reaction conditions: biphenylene (0.12 mmol), alkyne (0.10 mmol),
[MCl(cod)]2 (0.010 mmol), ligand (0.020 mmol), xylene (1.0 mL).
b The S- or S,S-isomer was used.
Table 2 Ir-Catalyzed Formal [4+2] Cycloaddition of Biphenylene with Various Alkynesa
Entry
Alkyne
Time (h) Product
Yield (%) ee (%)
Me
Me
Me
1
1b
2
18
11
2b
2c
2d
77
54
71
76
Me
OMe
2
3
1c
9
OMe
OMe
OMe
CF3
OMe
1d
92
OMe
CF3
Synlett 2008, No. 5, 765–768 © Thieme Stuttgart · New York

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Formal [4+2] Cycloaddition of Biphenylene and Alkynes
767
Table 2 Ir-Catalyzed Formal [4+2] Cycloaddition of Biphenylene with Various Alkynesa (continued)
Entry
Alkyne
Time (h) Product
Yield (%) ee (%)
CF3
OTBS
4
1e
3
2
2e
78
74
55
23
85
95
89
62
OTBS
CF3
CF3
Me
Me
5
1f
2f
CF3
CF3
6b
1g
24
2g
OMe
OMe
CF3
CF3
CO2Et
7b
1h
24
2h
CO2Et
CF3
a Reaction conditions: [IrCl(cod)2] (0.010 mmol), (S,S)-Me-BPE (0.020 mmol), biphenylene (0.12 mmol), alkyne (0.10 mmol), xylene (1.0 mL).
b Alkynes 1 were not completely consumed.
References and Notes
(1) Small Ring Compounds in Organic Synthesis VI, In Topics
in Current Chemistry; de Meijere, A., Ed.; Springer: Berlin,
1999.
(2) (a) Murakami, M.; Ito, Y. In Topics in Organometallic
Chemistry, Vol. 3; Murai, S., Ed.; Springer: New York,
1999, 97. (b) Rybtchinski, B.; Milstein, D. Angew. Chem.
Int. Ed. 1999, 38, 871. (c) Jun, C.-H. Chem. Soc. Rev. 2004,
33, 610.
(3) Perthuisot, C.; Edelbach, B. L.; Zubris, D. L.; Shimhai, N.;
Iverson, C. N.; Müller, C.; Satoh, T.; Jones, W. D. J. Mol.
Catal. A: Chem. 2002, 189, 157.
(4) (a) Eisch, J. J.; Piotrowski, A. M.; Han, K. I.; Krüger, C.;
Figure 1 The ORTEP diagram of the ferrocenyl ester derived from
cycloadduct 2g
Tsay, Y. H. Organometallics 1985, 4, 224. (b) Schwager,
H.; Spyroudis, S.; Vollhardt, K. P. C. J. Organomet. Chem.
1990, 382, 191. (c) Schaub, T.; Radius, U. Chem. Eur. J.
2005, 11, 5024. (d) Schaub, T.; Backes, M.; Radius, U.
Acknowlegment
This research was supported by a Grant-in-Aid for Scientific Rese-
Organometallics 2006, 25, 4196.
arch from the Ministry of Education, Culture, Sports, Science and
(5) (a) Lu, Z.; Jun, C.-H.; Gala, S. R.; Sigalas, M. P.; Eisenstein,
Technology, Japan.
O.; Crabtree, R. H. J. Chem. Soc., Chem. Commun. 1993,
1887. (b) Lu, Z.; Jun, C.-H.; Gala, S. R.; Sigalas, M. P.;
Eisenstein, O.; Crabtree, R. H. Organometallics 1995, 14,
1168.
(6) Perthuisot, C.; Jones, W. D. J. Am. Chem. Soc. 1994, 116,
3647.
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768
T. Shibata et al.
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130.7, 131.6, 132.7, 135.6, 138.0. Anal. Calcd for
(7) Perthuisot, C.; Edelbach, B. L.; Zubris, D. L.; Jones, W. D.
Organometallics 1997, 16, 2016.
(8) Edelbach, B. L.; Lachicotte, R. J.; Jones, W. D. J. Am. Chem.
Soc. 1998, 120, 2843.
(9) Yeh, W.-Y.; Hsu, S. C. N.; Peng, S.-M.; Lee, G.-H.
Organometallics 1998, 17, 2477.
(10) Yu, K.; Li, H.; Watson, E. J.; Virkaitis, K. L.; Carpenter, G.
B.; Sweigart, D. A. Organometallics 2001, 20, 3550.
(11) Iverson, C. N.; Jones, W. D. Organometallics 2001, 20,
5745.
C23H17F3O: C, 75.40; H, 4.68. Found: C, 75.47; H, 4.58.
HRMS–FAB (positive): m/z calcd for C23H17F3O: 366.1232
[M]+; found: 366.1198 [M]+; [a]D36 32.0 (c 1.00, CHCl3,
99% ee after recrystallization). The ee was determined by
chiral HPLC analysis using a chiral column (Daicel
Chiralpak IA-H: 4 × 250 mm, 254 nm UV detector, r.t.,
eluent: 0.5% 2-PrOH in hexane, flow rate: 0.5 mL/min, tR =
20 min for major isomer and 23 min for minor isomer).
(16) 9-Methyl-10-[(2-trifluoromethyl)phenyl]phenanthrene
(2f)
(12) In the presence of [IrCl(cod)]2 without diphosphine ligand,
alkyne 1a was consumed within 2 h, but the yield of 2a was
low (28%).
White solid; mp 109–111 °C. IR (CH2Cl2): 1315 cm–1. 1H
NMR (400 MHz, CDCl3): d = 2.37 (s, 3 H), 7.09 (d, J = 8.4
Hz, 1 H), 7.25 (d, J = 2.4 Hz, 1 H), 7.38–7.43 (m, 1 H), 7.55–
7.73 (m, 5 H), 7.89 (d, J = 8.4 Hz, 1 H), 8.13–8.16 (m, 1 H),
8.72 (d, J = 8.4 Hz, 1 H), 8.77–8.80 (m, 1 H). 13C NMR (100
MHz, CDCl3): d = 17.7, 122.3, 122.9, 125.1, 125.3, 125.7,
126.2, 126.3, 126.3, 126.5, 126.8, 127.2, 127.7, 129.1,
130.2, 130.7, 131.6, 131.9, 132.2, 132.4, 133.8, 139.5. Anal.
Calcd for C22H15F3: C, 78.56; H, 4.50. Found: C, 78.50; H,
4.40. HRMS–FAB (positive): m/z calcd for C22H15F3:
336.1126 [M]+; found: 336.1105 [M]+; [a]D26 –28.1 (c 1.00,
toluene, 98% ee after recrystallization). The ee was
determined by chiral HPLC analysis using a chiral column
(Daicel Chiralcel OD-H: 4 × 250 mm, 254 nm UV detector,
r.t., eluent: 1% 2-PrOH in hexane, flow rate: 1.0 mL/min,
tR = 8 min for minor isomer and 14 min for major isomer).
(17) (a) Shibata, T.; Fujimoto, T.; Yokota, K.; Takagi, K. J. Am.
Chem. Soc. 2004, 126, 8382. (b) Shibata, T.; Tsuchikama,
K. Chem. Commun. 2005, 6017. (c) Shibata, T.;
(13) General Experimental Procedure
[IrCl(cod)]2 (6.7 mg, 0.010 mmol) was placed in a 30 mL
two-neck flask under an argon atmosphere, and a xylene
solution (0.4 mL) of (S,S)-Me-BPE (5.2 mg, 0.020 mmol)
was added. After the mixture was stirred for 5 min at r.t., a
xylene solution (0.6 mL) of biphenylene (18.3 mg, 0.12
mmol) and an alkyne (0.10 mmol) was added. The mixture
was stirred at 100 °C, then the solvent was evaporated under
reduced pressure, and the resulting crude products were
purified by TLC to afford a pure cycloadduct.
(14) After being stirred for 4 h, cycloadduct 2c was obtained in
higher ee of 27% ee. Actually, gradual racemization of 2c
was ascertained at 100 °C.
(15) 9-Methoxymethyl-10-[(2-trifluoromethyl)phen-
yl]phenanthrene (2d)
White solid; mp 151–152 °C. IR (CH2Cl2): 1315, 1130,
1110, 1097 cm–1. 1H NMR (500 MHz, CDCl3): d = 3.25 (s,
3 H), 4.22 (d, J = 11.0 Hz, 1 H), 4.89 (d, J = 11.0 Hz, 1 H),
7.13 (d, J = 8.0 Hz, 1 H), 7.40–7.44 (m, 2 H), 7.60–7.72 (m,
5 H), 7.88 (d, J = 7.5 Hz, 1 H), 8.28–8.31 (m, 1 H), 8.73–
8.78 (m, 2 H). 13C NMR (100 MHz, CDCl3): d = 58.2, 70.4,
122.4, 122.8, 125.2, 126.1, 126.2, 126.4, 126.7, 126.8,
127.1, 128.0, 128.1, 129.7, 130.0, 130.2, 130.3, 130.6,
Tsuchikama, K.; Otsuka, M. Tetrahedron: Asymmetry 2005,
17, 614. (d) Shibata, T.; Arai, Y.; Takami, K.; Tsuchikama,
K.; Fujimoto, T.; Takebayashi, S.; Takagi, K. Adv. Synth.
Catal. 2006, 348, 2475. (e) Shibata, T.; Yoshida, S.; Arai,
Y.; Otsuka, M.; Endo, K. Tetrahedron 2008, 64, 821.
Synlett 2008, No. 5, 765–768 © Thieme Stuttgart · New York

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