Rhodium-catalyzed asymmetric conjugate alkynylation of nitroalkenes

Article abstract of DOI:10.1039/c0cc02181d

Asymmetric addition of (triisopropylsilyl)acetylene to nitroalkenes took place in the presence of a rhodium/chiral bisphosphine catalyst to give β-alkynylated nitroalkanes in high yields with high enantioselectivity.

Full text of DOI:10.1039/c0cc02181d

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Rhodium-catalyzed asymmetric conjugate alkynylation of nitroalkenesw
Takahiro Nishimura,* Takahiro Sawano, Sumito Tokuji and Tamio Hayashi*
Received 29th June 2010, Accepted 26th July 2010
DOI: 10.1039/c0cc02181d
Asymmetric addition of (triisopropylsilyl)acetylene to nitro-
alkenes took place in the presence of a rhodium/chiral
bisphosphine catalyst to give b-alkynylated nitroalkanes in high
yields with high enantioselectivity.
Nitroalkenes are known to be more reactive than enones
toward the conjugate addition,10 and successful examples of
the asymmetric addition have been reported for arylation11
and alkylation.12,13 Nevertheless, there has been only one
report on the asymmetric alkynylation of nitroalkenes to the
best of our knowledge. Thus, Tomioka et al. reported14 the
asymmetric addition of alkynylzinc reagents in the presence of
a stoichiometric amount of a chiral amino alcohol.
Transition metal-catalyzed asymmetric addition of terminal
alkynes to unsaturated bonds has substantial merit for the
synthesis of chiral internal alkynes in view of atom efficiency.1,2
An ideal process is the reaction of terminal alkynes in the
presence of a truly catalytic amount of a catalyst without using
a stoichiometric amount of pre-prepared alkynylmetal reagents.
The catalytic conjugate addition of terminal alkynes to a,b-
unsaturated carbonyl compounds is a challenging reaction
realizing high atom efficiency, and there have been several
reports on the addition to b-unsubstituted enones and enoates.3
In contrast, asymmetric conjugate alkynylation of enones and
related compounds bearing b-substituents,4 which is essential
for the creation of new stereogenic carbon centers at
b-position, has remained to be developed.5,6 In 2005, Carreira
et al. reported the first example of a catalytic asymmetric
conjugate addition of terminal alkynes using a chiral copper
catalyst, where the Michael acceptors are those derived from
Meldrum’s acid.7 In this context, we recently reported rhodium-
catalyzed asymmetric addition of (triisopropylsilyl)acetylene
to conjugated enones and enals, which requires only a rhodium
complex coordinated with a chiral bisphosphine ligand,
(R)-DTBM-segphos (Scheme 1).8,9 Here we report that nitro-
alkenes are another class of Michael acceptors suitable for the
rhodium-catalyzed asymmetric alkynylation.
A nitroalkene substituted with a phenyl group at the
b-position was found to be highly reactive toward the
rhodium-catalyzed alkynylation. The high reactivity is in
remarkable contrast to the low reactivity of b-phenyl-substituted
conjugated enones.15 As shown in Table 1, the reaction of
b-nitrostyrene (1a) with (triisopropylsilyl)acetylene (2o, 2 equiv.)
in 1,4-dioxane in the presence of Rh(OAc)((R)-DTBM-segphos)
(5 mol% of Rh), in situ generated from [Rh(OAc)(C2H4)2]2
and (R)-DTBM-segphos,16 at 80 1C for 12 h gave the addition
product 3ao in 94% yield with 97% ee (R)17 (entry 1). The
yield of 3ao was kept high (88%) in the alkynylation with a
reduced amount (1.2 equiv.) of 2o (entry 2). The reaction with
a lower catalyst loading (2 mol% of Rh) for a prolonged
reaction time gave the addition product in high yield (89%)
with high enantioselectivity (entry 3). A substituent on the
terminal alkyne had a great influence on the yield of the
addition product in the alkynylation of nitroalkenes, as it
has been already observed in the alkynylation of enones.8a
Thus, the addition of (tert-butyldimethylsilyl)acetylene (2p)
and (triethylsilyl)acetylene (2q) resulted in very low yields of
the corresponding addition products due to the alkyne
Table 1 Asymmetric addition of alkynes 2 to nitrostyrene (1a)a
Entry
R
Yieldb (%)
eec (%)
1
iPr3Si (2o)
iPr3Si (2o)
iPr3Si (2o)
tBuMe2Si (2p)
Et3Si (2q)
Ph (2r)
94 (3ao)
88 (3ao)
89 (3ao)
5 (3ap)f
5 (3aq)f
0 (3ar)
97 (R)
97 (R)
97 (R)
2d
3e
4
g
—
—
Scheme 1 Asymmetric conjugate alkynylation of enones and enals.
g
5
6
—
a
Reaction conditions: [Rh(OAc)(C2H4)2]2 (5 mol% of Rh), (R)-DTBM-
segphos (5.5 mol%), 1a (0.20 mmol), 2 (0.40 mmol), 1,4-dioxane (0.4 mL)
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 3983
b
c
at 80 1C for 12 h. Isolated yield. Determined by HPLC analysis with a
chiral stationary phase column: Chiralcel OD-H. Reaction with
d
e
1.2 equiv. of 2o. The reaction of 1a (1.0 mmol) with 2o (2.0 mmol) in
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. See DOI: 10.1039/
c0cc02181d
presence of the rhodium catalyst (2 mol% of Rh) in 1,4-dioxane (0.5 mL)
f
g
for 24 h. Determined by 1H NMR. Not determined.
c
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Chem. Commun., 2010, 46, 6837–6839 6837

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Table 2 Asymmetric addition of (triisopropylsilyl)acetylene (2o) to
nitroalkenes 1a
Scheme 2 Transformation of 3fo into 4ÁHCl. Reagents and conditions:
(a) TsOHÁH2O, EtOH, 70 1C; (b) Zn, Me3SiCl, EtOH, rt; (c) Bu4NF,
THF, rt; (d) HCl in Et2O.
Entry
R
Time/h Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
Ph (1a)
12
24
24
24
24
24
24
24
24
48
48
48
48
94 (3ao)
91 (3bo)
95 (3co)
95 (3do)
70 (3eo)
92 (3fo)
95 (3go)
88 (3ho)
99 (3io)
80 (3jo)
83 (3ko)
96 (3lo)
91 (3mo)
88 (3no)
97 (R)
98 (R)
97 (R)
97 (R)
95 (R)
97 (R)
97 (R)
98 (R)
97 (R)
92 (R)
94 (R)
99 (R)
97 (R)
92 (R)
4-MeC6H4 (1b)
3-MeC6H4 (1c)
2-MeC6H4 (1d)
4-MeOC6H4 (1e)
4-AcOC6H4 (1f)
4-ClC6H4 (1g)
4-CF3C6H4 (1h)
2-Naphthyl (1i)
Me (1j)
rhodium/(R)-DTBM-segphos catalyst giving the addition
products in high yields with high enantioselectivity.
This work was supported by a Grant-in-Aid for Scientific
Research (S) (19105002) from the MEXT, Japan. We
thank Takasago International Corporation for the gift of
(R)-DTBM-segphos.
9
10
11
12
13
14
Et (1k)
iPr (1l)
Cyclohexyl (1m)
Notes and references
4-MeOC6H4CH2OCH2 (1n) 48
1 For reviews, see: (a) B. M. Trost and A. H. Weiss, Adv. Synth.
Catal., 2009, 351, 963; (b) S. Fujimori, T. F. Knopfel, P. Zarotti,
a
Reaction conditions: [Rh(OAc)(C2H4)2]2 (5 mol% of Rh),
(R)-DTBM-segphos (5.5 mol%), 1 (0.20 mmol), 2o (0.40 mmol),
¨
T. Ichikawa, D. Boyall and E. M. Carreira, Bull. Chem. Soc. Jpn.,
2007, 80, 1635; (c) L. Zani and C. Bolm, Chem. Commun., 2006,
4263; (d) P. G. Cozzi, R. Hilgraf and N. Zimmermann, Eur. J. Org.
Chem., 2004, 4095; (e) C. Wei, Z. Li and C.-J. Li, Synlett, 2004,
1472; (f) L. Pu, Tetrahedron, 2003, 59, 9873; (g) D. E. Frantz,
b
c
1,4-dioxane (0.4 mL) at 80 1C. Isolated yield. Determined by HPLC
analysis. The absolute configuration of 3fo was determined to be R
(Scheme 2). For others, they were assigned by analogy with entry 6.
R. Fassler, C. S. Tomooka and E. M. Carreira, Acc. Chem. Res.,
¨
2000, 33, 373.
dimerization (entries 4 and 5). In the reaction of phenylacetylene
(2r), the formation of the corresponding addition product was
not observed (entry 6).
2 (a) B. M. Trost, Science, 1991, 254, 1471; (b) B. M. Trost, Angew.
Chem., Int. Ed. Engl., 1995, 34, 259; (c) B. M. Trost, M. T. Sorum,
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119, 698.
¨
Table 2 summarizes the results obtained for the reactions of
several nitroalkenes 1 with (triisopropylsilyl)acetylene (2o).
The addition to b-nitrostyrenes substituted with a methyl
group at para- (1b), meta- (1c), and ortho-position (1d) on
the benzene ring all gave the corresponding addition products
with high enantioselectivities (entries 2–4). The present catalytic
asymmetric alkynylation was also successful for nitroalkenes
substituted with aromatic groups bearing methoxy (1e), acetoxy
(1f), chloro (1g), and trifluoromethyl (1h), and with 2-naphthyl
group (1i) giving the corresponding addition products
(3eo–3io) with over 95% ee (entries 5–9). Nitroalkenes
substituted with primary alkyl groups, methyl (1j) and ethyl
(1k), secondary alkyl groups, isopropyl (1l) and cyclohexyl
(1m), and a functionalized alkyl group (1n) are also good
substrates to give the corresponding addition products 3jo–3no
in high yields with high enantioselectivity (entries 10–14).18
The b-alkynylated nitroalkanes obtained here with high
enantioselectivity are readily converted into b-ethynyl
alkylamines without loss of enantiomeric purity (Scheme 2).
For example, deacetylation of 3fo followed by reduction of the
nitro group into amino by treatment with Zn/ClSiMe3 in
ethanol,19 and desilylation gave b-ethynyltyramine 4 (80%
yield as 4ÁHCl),20 which is an inhibitor of dopamine b-hydro-
xylase.21 The absolute configuration of 3fo was determined to
be R-(À) by correlation with (S)-4ÁHCl ([a]2D0 À15.3 (c 1.00,
DMF) for 97% ee (S); lit.21b [a]2D5 À17.1 (c 1.5, DMF) for
(S)-4ÁHCl).
3 Ru: (a) M. Picquet, C. Bruneau and P. H. Dixneuf, Tetrahedron,
1999, 55, 3937; (b) S. Chang, Y. Na, E. Choi and S. Kim, Org.
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Y. Nishiguchi, Y. Maeda and S. Uemura, Chem. Commun., 2004,
1312; (d) T. Nishimura, Y. Washitake and S. Uemura, Adv. Synth.
Catal., 2007, 349, 2563; Rh: (e) G. I. Nikishin and I. P. Kovalev,
Tetrahedron Lett., 1990, 31, 7063; (f) R. V. Lerum and
J. D. Chisholm, Tetrahedron Lett., 2004, 45, 6591; Pd:
(g) L. Chen and C.-J. Li, Chem. Commun., 2004, 2362.
4 (a) T. F. Knopfel and E. M. Carreira, J. Am. Chem. Soc., 2003,
¨
¨
125, 6054; (b) T. F. Knopfel, D. Boyall and E. M. Carreira, Org.
Lett., 2004, 6, 2281; (c) S. Fujimori and E. M. Carreira, Angew.
Chem., Int. Ed., 2007, 46, 4964.
5 For examples of catalytic enantioselective addition of pre-prepared
alkynylmetal reagents to alkenes, see: (a) Y.-S. Kwak and
E. J. Corey, Org. Lett., 2004, 6, 3385; (b) O. V. Larionov and
E. J. Corey, Org. Lett., 2010, 12, 300; (c) T. R. Wu and
J. M. Chong, J. Am. Chem. Soc., 2005, 127, 3244; (d) S. Crotti,
F. Bertolini, F. Macchia and M. Pineschi, Chem. Commun., 2008,
3127.
6 For an example of nickel-catalyzed asymmetric alkynylation of
conjugated dienes, see: M. Shirakura and M. Suginome, Angew.
Chem., Int. Ed., 2010, 49, 3827.
7 T. F. Knopfel, P. Zarotti, T. Ichikawa and E. M. Carreira, J. Am.
¨
Chem. Soc., 2005, 127, 9682.
8 (a) T. Nishimura, X.-X. Guo, N. Uchiyama, T. Katoh and
T. Hayashi, J. Am. Chem. Soc., 2008, 130, 1576;
(b) T. Nishimura, T. Sawano and T. Hayashi, Angew. Chem.,
Int. Ed., 2009, 48, 8057.
9 Forrecent examples of rhodium-catalyzed asymmetric alkynyla-
tion, see: (a) E. Fillion and A. K. Zorzitto, J. Am. Chem. Soc.,
2009, 131, 14608; (b) P. K. Dhondi, P. Carberry, L. B. Choi and
J. D. Chisholm, J. Org. Chem., 2007, 72, 9590; (c) H. Nishiyama
and J. Ito, Chem. Commun., 2010, 46, 203.
In summary, we have succeeded in a conjugate addition
of (triisopropylsilyl)acetylene to nitroalkenes by use of a
10 For a review, see: O. M. Berner, L. Tedeschi and D. Enders, Eur. J.
Org. Chem., 2002, 1877.
c
6838 Chem. Commun., 2010, 46, 6837–6839
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11 (a) T. Hayashi, T. Senda and M. Ogasawara, J. Am. Chem. Soc.,
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9, 1341; (b) A. Duursma, A. J. Minnaard and B. L. Feringa,
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15 The reaction of 4-phenylbut-3-en-2-one with 2o under the same
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addition product in 14% yield (NMR).
Lett., 2004, 6, 2689; (f) A. Cote
´
,
V. N. G. Lindsay and
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17 The absolute configuration of 3ao was assigned by analogy with
3fo in entry 6 of Table 2 and Scheme 2.
18 The reaction of 1-nitrocyclohex-1-ene gave no addition product.
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20 Enantiomeric excess of 4 was determined by HPLC analysis of
4-(1-acetamidobut-3-yn-2-yl)phenyl acetate derived from 4.
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c
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Chem. Commun., 2010, 46, 6837–6839 6839