Cobalt-catalyzed asymmetric addition of silylacetylenes to oxa- and azabenzonorbornadienes

Article abstract of DOI:10.1039/c2cc31880f

Asymmetric addition of silylacetylenes to meso-oxa- and azabenzonorbornadienes took place in the presence of a cobalt/QuinoxP* catalyst to give the addition products in good yields with high enantioselectivity.

Full text of DOI:10.1039/c2cc31880f

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COMMUNICATION
Cobalt-catalyzed asymmetric addition of silylacetylenes to oxa- and
azabenzonorbornadienesw
Takahiro Sawano, Keiyu Ou, Takahiro Nishimura* and Tamio Hayashi*
Received 14th March 2012, Accepted 25th April 2012
DOI: 10.1039/c2cc31880f
Asymmetric addition of silylacetylenes to meso-oxa- and
azabenzonorbornadienes took place in the presence of a cobalt/
QuinoxP* catalyst to give the addition products in good yields with
high enantioselectivity.
complexes in the addition of silylacetylenes to oxabenzo-
norbornadienes, and we found that the alkynylation proceeds
without the ring-opening to give hydroalkynylation products.
Thus, treatment of oxabenzonorbornadiene 1a with 2 equiv. of
(triisopropylsilyl)acetylene (2m) in the presence of Co(OAc)2ꢀ
4H2O (5 mol%), 1,2-bis(diphenylphosphino)ethane (dppe)
(5 mol%), and zinc powder (50 mol%) in dimethyl sulfoxide
(DMSO) at 80 1C for 20 h, which are standard conditions for
the cobalt-catalyzed alkynylation of enones, gave 1,2,3,4-
tetrahydro-2-alkynyl-1,4-epoxynaphthalene 3am in 73% yield
(Table 1, entry 1). For the development of an asymmetric
variant of this reaction, several chiral bisphosphine ligands
were tested (entries 2–7). A cobalt/(S,S)-chiraphos catalyst
efficiently catalyzed the present reaction to give 3am in 84%
yield, but the ee was moderate (54% ee, entry 2). The use of
(S,S)-bdpp, which enables the cobalt-catalyzed asymmetric alkynyl-
ation of conjugated enones with high enantioselectivity,11 gave a
low yield of 3am (17% yield, entry 3). Some other chiral bisphos-
phine ligands were examined (entries 4–7), and (R,R)-QuinoxP*2d
was found to show the highest enantioselectivity (67% ee,
entry 7).12 The reaction temperature significantly affected
both the yield and the enantioselectivity (entries 8 and 9).
Thus, the reaction by use of (R,R)-QuinoxP* at 10 1C
proceeded to give 3am in 90% yield with 99% ee (entry 9).
The yield and enantioselectivity of 3am were kept high (91%,
99% ee) in the reaction with a reduced amount (10 mol%) of
zinc powder (entry 10). The reaction in the absence of zinc
gave only 21% yield of 3am (entry 11), implying that an active
catalytic species is formed by reduction of cobalt(II) acetate
with zinc.11
Transition metal-catalyzed desymmetrization of meso-bicyclic
alkenes is a fundamentally important reaction for the synthesis
of chiral building blocks.1 Palladium- and rhodium-catalyzed
asymmetric transformations of oxa- and azabicyclic alkenes
have been extensively studied, where enantioposition-selective
addition of oxygen, nitrogen, and carbon nucleophiles brings
about desymmetrization of their meso structures and subsequent
ring-opening reactions provide access to enantioenriched com-
pounds bearing multiple stereocenters in a single step.2–5 Of several
carbon nucleophiles, organozinc and -boron reagents have been
often used in the asymmetric addition to meso-bicyclic alkenes,
while the asymmetric addition of terminal alkynes remains to be
developed. In 2002, Cheng and co-workers reported the first
nickel-catalyzed ring-opening alkynylation of oxa- and azabicyclic
alkenes, where racemic 2-alkynyl-1,2-dihydronaphthalene
derivatives were produced in high yields with high diastereo-
selectivity.6 Rhodium-catalyzed asymmetric alkynylations of
azabenzonorbornadienes7 and bicyclic hydrazines8 involving the
ring-opening were also reported. On the other hand, Tenaglia et al.
reported hydroalkynylation of oxabenzonorbornadienes without
the ring-opening, which is catalyzed by a phosphapalladacycle
complex giving racemic 2-alkynyl-1,2,3,4-tetrahydro-1,4-epoxy-
naphthalenes.9,10 Here we report the first example of catalytic
asymmetric addition of terminal alkynes to oxabenzonorborna-
dienes without the ring-opening, which was achieved by use of a
chiral phosphine–cobalt catalyst system.
Table 2 summarizes the results obtained from the reaction
of several oxabenzonorbornadienes 1 with silylacetylenes 2,
which was carried out in the presence of cobalt/(R,R)-QuinoxP*
as a catalyst (5 mol%). The reaction of meso-oxabenzonorborna-
dienes 1a–1f bearing substituents (Me, F, Br, and OMe) on the
benzene ring gave the corresponding addition products 3am–3fm
in high yields with high enantioselectivity (90–99% ee) (entries
1–6). The present cobalt-catalyzed alkynylation can introduce
bulky silylacetylene 2n with high enantioselectivity (entries 7 and
8), but the addition of less bulky (triethylsilyl)acetylene (2o) to 1a
gave only 7% of the addition product 3ao (entry 9) and
phenylacetylene (2p) and 1-octyne (2q) were not applicable
(entries 10 and 11). Azabenzonorbornadienes 1g and 1h were
also good substrates in the addition of 2m to give 3gm and 3hm
We recently reported cobalt-catalyzed addition of silylacety-
lenes to a,b-unsaturated ketones giving b-alkynyl ketones.11 As
a part of our continuing efforts in developing cobalt-catalyzed
reactions, we examined the catalytic activity of cobalt(I)
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 3988; Tel: +81 75 753 3987
w Electronic supplementary information (ESI) available: Experimental
procedures, compound characterization data, and X-ray crystallo-
graphic data of compound 6. CCDC 865189. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c2cc31880f
c
6106 Chem. Commun., 2012, 48, 6106–6108
This journal is The Royal Society of Chemistry 2012

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Table 1 Cobalt-catalyzed asymmetric alkynylation of oxabenzo-
norbornadiene 1aa
Table 2 Asymmetric alkynylation of oxa- and azabenzonorbornadienea
Entry
X
R1 R2
R3
Yieldb (%) eec (%)
1
O
O
O
O
O
O
O
O
O
O
O
NBoc
H
H (1a)
Me H (1b)
Si(i-Pr)3 (2m)
Si(i-Pr)3 (2m)
Si(i-Pr)3 (2m)
Si(i-Pr)3 (2m)
91 (3am)
82 (3bm)
86 (3cm)
81 (3dm)
70 (3em)
91 (3fm)
99
99
90
94
95
97
90g
96
80
—
—
96g
95g
2d
3d,e
4d,e
5d,e
6
F
Br H (1d)
Br Me (1e) Si(i-Pr)3 (2m)
H OMe (1f) Si(i-Pr)3 (2m)
H (1c)
7d,f
8
Br Me (1e) SiPh2(t-Bu) (2n) 60 (3en)
H
H
H
H
H
OMe (1f) SiPh2(t-Bu) (2n) 90 (3fn)
9
H (1a)
H (1a)
H (1a)
H (1g)
SiEt3 (2o)
Ph (2p)
C6H13 (2q)
Si(i-Pr)3 (2m)
Si(i-Pr)3 (2m)
7 (3ao)
0 (3ap)
0 (3aq)
73 (3gm)
70 (3hm)
10
11
12d
Entry Ligand
Temp./1C Conv.b (%) Yieldc (%) eed (%)
13d,f NBoc Me H (1h)
1
2
3
4
5
6
7
8
dppe
80
80
80
80
80
96
100
39
10
62
100
100
98
100
92
73
84
17
1
45
36
21
53
90
91
21
—
54
11
—
20
4
67
95
99
99
98
a
Reaction conditions:
1
(0.20 mmol), alkyne 2 (0.40 mmol),
(S,S)-chiraphos
(S,S)-bdpp
(R)-binap
Co(OAc)2ꢀ4H2O (5 mol%), (R,R)-QuinoxP* (5 mol%), Zn
e
b
(10 mol%), DMSO (0.30 mL) at 10 1C for 20 h. Isolated yield of 3.
Determined by chiral HPLC analysis. For 48 h. Reaction at
c
d
e
(R,R)-dipamp
f
g
(S,S)-Me-Duphos 80
(R,R)-QuinoxP* 80
(R,R)-QuinoxP* 40
(R,R)-QuinoxP* 10
(R,R)-QuinoxP* 10
(R,R)-QuinoxP* 10
15 1C. Reaction at 30 1C. ee values were determined by chiral
HPLC analysis of desilylated products of 3.
9
10f
11g
25
a
Reaction conditions: 1a (0.20 mmol), (triisopropylsilyl)acetylene
(2m) (0.40 mmol), Co(OAc)2ꢀ4H2O (5 mol%), ligand (5 mol%), Zn
b
(50 mol%), DMSO (0.3 mL) for 20 h. Conversion of 1a determined
by 1H NMR. Isolated yield. Determined by chiral HPLC analysis.
c
d
e
f
Not determined. Zn (10 mol%) was used. Performed without Zn.
g
in 73% and 70% yield with 96% and 95% ee, respectively
(entries 12 and 13).
Fig. 1 ORTEP illustration of compound 6 with thermal ellipsoids
drawn at the 50% probability level.
obtained by treatment of 3em with tetrabutylammonium
fluoride (eqn (2), Fig. 1).14
To gain information about the catalytic cycle, we carried
out deuterium labeling experiments starting with deuterated
silylacetylenes. The reaction of oxabenzonorbornadiene 1f
with the deuterated alkyne 2m-d under the standard reaction
conditions gave 3fm-d, which showed 97% of deuterium-
incorporation at the 3-exo-position (eqn (3)).15 On the other hand,
treatment of 1f with an equimolar mixture of the deuterated alkyne
2m-d and (tert-butyldiphenysilyl)acetylene (2n) gave addition
ð1Þ
ð2Þ
The same type of addition was observed in the reaction of
oxanorbornadiene 4 with alkyne 2m to give hydroalkynylation
product 5 in 60% yield with 95% ee (eqn (1)).13
The relative and absolute configuration of 3em was deter-
mined to be 1S,2R,4R by X-ray analysis of 6, which was
ð3Þ
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6106–6108 6107

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Germany, 2005, ch. 10; (b) M. Lautens, K. Fagnou and S. Hiebert,
Acc. Chem. Res., 2003, 36, 48; (c) M. Lautens, K. Fagnou, M. Taylor
and T. Rovis, J. Organomet. Chem., 2001, 624, 259.
2 Pd-catalyst, see: (a) M. Lautens, J.-L. Renaud and S. Hiebert,
J. Am. Chem. Soc., 2000, 122, 1804; (b) M. Lautens, S. Hiebert and
J.-L. Renaud, J. Am. Chem. Soc., 2001, 123, 6834; (c) M. Lautens
and S. Hiebert, J. Am. Chem. Soc., 2004, 126, 1437;
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2005, 127, 11934; (e) S. Cabrera, R. Gomez, I. Alonso and
´
J. C. Carretero, J. Am. Chem. Soc., 2005, 127, 17938;
(f) H. A. McManus, M. J. Fleming and M. Lautens, Angew.
Chem., Int. Ed., 2007, 46, 433; (g) M. J. Fleming,
H. A. McManus, A. Rudolph, W. H. Chan, J. Ruiz,
C. Dockendorff and M. Lautens, Chem.–Eur. J., 2008, 14, 2112.
3 Rh-catalyst, see: (a) M. Lautens, K. Fagnou and T. Rovis, J. Am.
Chem. Soc., 2000, 122, 5650; (b) M. Lautens and K. Fagnou,
Tetrahedron, 2001, 57, 5067; (c) M. Lautens and K. Fagnou, J. Am.
Chem. Soc., 2001, 123, 7170; (d) M. Lautens, C. Dockendorff,
K. Fagnou and A. Malicki, Org. Lett., 2002, 4, 1311;
(e) M. Lautens, K. Fagnou and V. Zunic, Org. Lett., 2002,
4, 3465; (f) M. Lautens, K. Fagnou and D. Yang, J. Am. Chem.
Soc., 2003, 125, 14884; (g) Y.-H. Cho, V. Zunic, H. Senboku,
M. Olsen and M. Lautens, J. Am. Chem. Soc., 2006, 128, 6837;
Scheme 1 Proposed catalytic cycle.
products 3fm and 3fn in 39% and 54% yield, respectively, where
both products partially contained deuterium (H/D = 1.3 for 3fm
and H/D = 1.4 for 3fn) (eqn (4)).16 These results indicate that
hydroalkynylation proceeds via syn-addition of the terminal alkyne
and the terminal proton is the hydrogen source of the addition
product. In addition, the observed scrambling between hydrogen
and deuterium implies that the present alkynylation includes
carbometalation and protonation steps (vide infra).
(h) R. Webster, C. Boing and M. Lautens, J. Am. Chem. Soc., 2009,
¨
131, 444; (i) A. Boyer and M. Lautens, Angew. Chem., Int. Ed.,
2011, 50, 7346.
4 Cu-catalyst, see: (a) F. Bertozzi, M. Pineschi, F. Macchia,
L. A. Arnold, A. J. Minnaard and B. L. Feringa, Org. Lett.,
2002, 4, 2703; (b) W. Zhang, L.-X. Wang, W.-J. Shi and
Q.-L. Zhou, J. Org. Chem., 2005, 70, 3734.
5 For examples of asymmetric cyclodimerization of oxa- and azabicyclic
alkenes, see: (a) T. Nishimura, T. Kawamoto, K. Sasaki, E. Tsurumaki
and T. Hayashi, J. Am. Chem. Soc., 2007, 129, 1492; (b) A. Allen,
P. L. Marquand, R. Burton, K. Villeneuve and W. Tam, J. Org.
Chem., 2007, 72, 7849.
6 (a) D. K. Rayabarapu, C.-F. Chiou and C.-H. Cheng, Org. Lett.,
2002, 4, 1679; (b) For related examples, see: D.-J. Huang,
D. K. Rayabarapu, L.-P. Li, T. Sambaiah and C.-H. Cheng,
Chem.–Eur. J., 2000, 6, 3706(c) D. K. Rayabarapu, T. Sambaiah
and C.-H. Cheng, Angew. Chem., Int. Ed., 2001, 40, 1286;
(d) K. C. Chao, D. K. Rayabarapu, C.-C. Wang and
C.-H. Cheng, J. Org. Chem., 2001, 66, 8804; (e) D. K.
Rayabarapu and C.-H. Cheng, Chem.–Eur. J., 2003, 9, 3164;
(f) M.-S. Wu, D. K. Rayabarapu and C.-H. Cheng, J. Org. Chem.,
2004, 69, 8407; (g) D. K. Rayabarapu and C.-H. Cheng, Acc.
Chem. Res., 2007, 40, 971.
7 T. Nishimura, E. Tsurumaki, T. Kawamoto, X.-X. Guo and
T. Hayashi, Org. Lett., 2008, 10, 4057.
8 S. Crotti, F. Bertolini, F. Macchia and M. Pineschi, Chem.
Commun., 2008, 3127.
ð4Þ
Scheme 1 illustrates the catalytic cycle proposed for the
present cobalt-catalyzed alkynylation. It is likely that the
catalytic reaction is initiated by the reduction of cobalt(II) to
cobalt(I) by zinc powder giving a cobalt(I) acetate A,17 which
undergoes the reaction with a terminal alkyne to form an
alkynylcobalt(I) B and acetic acid.18 An approach of the
alkynylcobalt B from the exo direction of oxabenzonorbornadiene
followed by syn-carbometalation to form an alkylcobalt(I) species
C. Protonation of alkylcobalt C with the terminal alkyne gives
the alkynylation product and regenerates the alkynylcobalt
intermediate B.
9 A. Tenaglia, L. Giordano and G. Buokno, Org. Lett., 2006,
8, 4315.
10 For examples of alkynylation of norbornene, see: (a) K. Kohno,
K. Nakagawa, T. Yahagi, J.-C. Choi, H. Yasuda and T. Sakakura,
J. Am. Chem. Soc., 2009, 131, 2784; (b) K. Ogata, J. Sugasawa,
Y. Atsuumi and S.-i. Fukuzawa, Org. Lett., 2010, 12, 148.
11 T. Nishimura, T. Sawano, K. Ou and T. Hayashi, Chem. Commun.,
2011, 47, 10142.
12 Naphthalene (12%) and 2-((triisopropylsilyl)ethynyl)naphthalene
(11%) formed were observed as side products.
13 The alkynylation of benzonorbornadiene or norbornadiene did not
take place.
14 The absolute configurations of other products were assigned by
analogy with 3em.
In summary, we have developed a cobalt-catalyzed addition of
silylacetylenes to oxa- and azabenzonorbornadienes giving the
corresponding addition products with high enantioselectivity.
T.S. thanks the JSPS for Young Scientists for a research
fellowship.
15 Co(OAc)2 was used instead of Co(OAc)2ꢀ4H2O to avoid the
incorporation of protons.
16 After treatment of an equimolar amount of 2m-d and 2n without
oxabenzonorbornadiene 1f under the same reaction conditions, a
partial H/D exchange was observed for recovered 2n (81% yield,
H/D = 4).
17 (a) M. Jeganmohan and C.-H. Cheng, Chem.–Eur. J., 2008,
´
14, 10876; (b) C. Gosmini, J.-M. Begouin and A. Moncomble,
Chem. Commun., 2008, 3221.
18 G. Albertin, S. Antoniutti, A. Bacchi, E. Bordignon and G. Pelizzi,
Organometallics, 1995, 14, 4126.
Notes and references
1 For reviews, see: (a) K. Fagnou, in Modern Rhodium-Catalyzed
Organic Reactions, ed. P. A. Evans, Wiley-VCH, Weinheim,
c
6108 Chem. Commun., 2012, 48, 6106–6108
This journal is The Royal Society of Chemistry 2012