Chiral amino alcohol-mediated asymmetric conjugate addition of arylalkynes to nitroolefins

Article abstract of DOI:10.1021/ol050643p

(Chemical Equation Presented) The asymmetric reaction of nitroolefins with arylalkynes was mediated by dimethylzinc (or diethylzinc) and (1R,2R)-2-(dimethylamino)-1,2-diphenylethanol in toluene to provide the corresponding conjugate alkynylation products

Full text of DOI:10.1021/ol050643p

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2369-2371
Chiral Amino Alcohol-Mediated
Asymmetric Conjugate Addition of
Arylalkynes to Nitroolefins
Mitsuaki Yamashita, Ken-ichi Yamada, and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
tomioka@pharm.kyoto-u.ac.jp
Received March 25, 2005
ABSTRACT
The asymmetric reaction of nitroolefins with arylalkynes was mediated by dimethylzinc (or diethylzinc) and (1R,2R)-2-(dimethylamino)-1,2-
diphenylethanol in toluene to provide the corresponding conjugate alkynylation products with high enantiomeric excess of up to 99% in good
yields. The presence of 0.03 equiv of galvinoxyl improved the reaction yield.
The asymmetric addition of alkynes to an electron-deficient
double bond has been the recent focus of asymmeric
reactions.1 Aldehydes,2-5 ketones,6-8 and imines9-12 are
electrophiles that have been well documented by many
groups. On the other hand, R,â-unsaturated carbonyl com-
pounds or their congeners are acceptors that have seldom
accomplished high enantioselectivity.13-15 The catalytic
asymmetric conjugate alkynylation of enones recently re-
(1) Review: (a) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org.
Chem. 2004, 4095-4105. (b) Pu, L. Tetrahedron 2003, 59, 9873-9886.
(2) Lithium acetylide: Mukaiyama, T.; Suzuki, K.; Soai, K.; Sato, T.
Chem. Lett. 1979, 447-448.
(8) Catalytic addition of zinc acetylide: (a) Liu, L.; Wang, R.; Kang,
Y.-F.; Chen, C.; Xu, Z.-Q.; Zhou, Y.-F.; Ni, M.; Cai, H.-Q.; Gong, M.-Z.
J. Org. Chem. 2005, 70, 1084-1086. (b) Kang, Y.-F.; Liu, L.; Wang, R.;
Zhou, Y.-F.; Yan, W.-J. AdV. Synth. Catal. 2005, 347, 243-247. (c) Zhou,
Y.-F.; Wang, R.; Xu, Z.-Q.; Yan, W.-J.; Liu, L.; Kang, Y.-F.; Han, Z.-J.
Org. Lett. 2004, 6, 4147-4149. (d) Liu, L.; Kang, Y.-F.; Wang, R.; Zhou,
Y.-F.; Chen, C.; Ni, M.; Gong, M.-Z. Tetrahedron: Asymmetry 2004, 15,
3757-3761. (e) Saito, B.; Katsuki, T. Synlett 2004, 1557-1560. (f) Lu,
G.; Li, X.; Jia, X.; Chan, W. L.; Chan, A. S. C. Angew. Chem., Int. Ed.
2003, 42, 5057-5058. (g) Cozzi, P. G. Angew. Chem., Int. Ed. 2003, 42,
2895-2898.
(3) Alkynylborane: Corey, E. J.; Cimprich, K. A. J. Am. Chem. Soc.
1994, 116, 3151-3152.
(4) Recent catalytic addition of zinc acetylide using dialkylzinc: (a) Kang,
Y.-F.; Liu, L.; Wang, R.; Yan, W.-J.; Zhou, Y.-F. Tetrahedron: Asymmetry
2004, 15, 3155-3159. (b) Dahmen, S. Org. Lett. 2004, 6, 2113-2116. (c)
Li, Z.-B.; Pu, L. Org. Lett. 2004, 6, 1065-1068. (d) Marshall, J. A.;
Bourbeau, M. P. Org. Lett. 2003, 5, 3197-3199. (e) Kamble, R. M.; Singh,
V. K. Tetrahedron Lett. 2003, 44, 5347-5349. (f) Li, X.-S.; Lu, G.; Kwok,
W. H.; Chan, A. S. C. J. Am. Chem. Soc. 2002, 124, 12636-12637. (g)
Braga, A. L.; Appelt, H. R.; Silveira, C. C.; Wessjohann, L. A.; Schneider,
P. H. Tetrahedron 2002, 58, 10413-10416.
(5) Catalytic addition of zinc acetylide using Zn(OTf)2: (a) Jiang, B.;
Chen, Z.; Xiong, W. J. Chem. Soc., Chem. Commun. 2002, 1524-1525.
(b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687-
9688. (c) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806-1807.
(6) Lithium acetylide: (a) Scharpwinkel, K.; Matull, S.; Schafer, H. J.
Tetrahedron: Asymmetry 1996, 7, 2497-2500. (b) Thompson, A. S.; Corley,
E. G.; Huntington, M. F.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36,
8937-8940.
(7) Zinc acetylide: Tan, L.; Chen, C.-Y.; Tillyer, R. D.; Grabowski, E.
J. J.; Reider, P. J. Angew. Chem., Int. Ed. 1999, 38, 711-713.
(9) Addition of lithium acetylide to ketimine: Huffman, M. A.; Yasuda,
N.; DeCamp, A. E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590-
1594.
(10) Catalytic addition of copper acetylide to enamine: Koradin, C.;
Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 2535-2538.
(11) Catalytic addition of copper acetylide: (a) Kno¨pfel, T. F.; Aschwanden,
P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem., Int. Ed.
2004, 43, 5971-5973. (b) Benaglia, M.; Negri, D.; Dell’Anna, G.
Tetrahedron. Lett. 2004, 45, 8705-8708. (c) Gommermann, N.; Koradin,
C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763-5766.
(d) Wei, C.; Li, C. W. J. Am. Chem. Soc. 2002, 124, 5638-5639.
(12) Catalytic addition of zinc acetylide: Traverse, J. F.; Hoveyda, A.
H.; Snapper, M. L. Org. Lett. 2003, 5, 3273-3275.
(13) Asymmetric conjugate addition of chiral boron acetylide: Chong,
J. M.; Shen, L.; Taylor, N. J. J. Am. Chem. Soc. 2000, 122, 1822-1823.
10.1021/ol050643p CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/10/2005

ported by Corey and Chong is the exception.16 We describe
herein that arylalkynes undergo conjugate addition reaction
with nitroolefins to provide the corresponding alkynylation
adducts with high enantioselectivities of up to 99% ee.
Our approach began with the application of the chiral
ligand-controlled asymmetric conjugate addition reaction of
aryllithiums with nitroolefins.17,18 The reaction of lithiated
trityl ether of propargyl alcohol 2a with nitroolefin 1a in
the presence of a tridentate chiral amino ether ligand 3a in
toluene, however, gave the addition product 4a with a
marginal ee of 7% in 96% yield. Reaction of heteroaggre-
gated lithium acetylide of 2a with a chiral amino alcohol
3b, the starting material for the preparation of 3a,17b was
not successful, giving 4a with 4% ee in 92% yield.
yield (Table 1, entry 1). The enantiomeric excess was
determined by chiral stationary phase HPLC (Daicel Chiral-
cel OD-H, hexane/i-PrOH ) 100/1; See Supporting Informa-
tion). The yield was slightly improved by the addition of
0.1 equiv of poly(ethylene glycol) dimethyl ether (DMPEG)19
at room temperature for 120 h to give 4b with 96% ee in
52% yield (entry 2). Screening of solvents (DMSO, THF,
acetonitrile, CH2Cl2) was not fruitful, giving 4b with 96-
97% ee in 19-43% yield.
Improvement of the yield was achieved by using 3 equiv
each of 2b, 3b, and dimethylzinc in toluene at 50 °C for 10
h to give 4b with 95% ee in 66% yield (entry 3). Much more
improvement was obtained upon addition of 0.03 equiv of
galvinoxyl to scavenge radicals,20 giving, after 30 h at room
temperature, a 73:27 mixture of trans- and cis-4b with 97
and 96% ee, respectively, in 83% yield (entry 4). Dimeth-
ylzinc was replaceable with diethylzinc to give 4b in
comparable enantioselectivity and yield (entry 5). It is also
important to note that in the absence of chiral amino alcohol
3b, the reaction at 50 °C for 15 h gave 4b in less than 5%
yield (entry 6).
Promising results were obtained by changing the metal
from lithium to zinc (Table 1). The reaction of 1.5 equiv of
Table 1. Amino Alcohol 3b-Mediated Asymmetric Conjugate
Addition of 2b to 1a Giving 4b
It is important to note that saturated ammonium chloride
quench of the reaction gave a trans major 73:27 mixture of
4b, while acetic acid quench favored cis-4b in a ratio of
81:19. Isomerization of pure cis-4b of 94% ee was possible
by treatment with triethylamine in acetonitrile at room
temperature for 24 h to give 4b as a trans major 71:29
mixture in 95% yield without any racemization.
The chirality controller of amino alcohol 3b is recoverable
in 95% yield by collecting its crystalline hydrochloride after
10% hydrochloric acid treatment of the quenched reaction
mixture and is reusable in the asymmetric reaction.
Linear nitroolefins 1b-d (R ) n-Bu, i-Pr, t-Bu) were also
reacted with phenylacetylene 2b under the established
conditions as above to give the corresponding conjugate
alkynylation products 5b-d with 98, 96, and 98% ee,
respectively, in moderate to good yields (Table 2). The
moderate yields in entries 1 and 2 are due to concomitant
deprotonation and isomerization of double bond of 1b and
1c.
2b
3b
Me2Zn temp time yield
ee
entry (equiv) (equiv) (equiv)
(°C)
(h)
(%)a (%)b
1
1.5
1.5
3
3
3
1.5
1.5
3
3
3
1.5
1.5
3
3
3
50
rt
50
rt
rt
24
120
10
30
30
39
52
66
83
74
<5
95
96
95
97
97
2c
3
4d
5d,e
6
3
0
3
50
15
a Combined yield. b Ee (%) of trans-4b. c DMPEG (0.1 equiv) was used.
d Galvinoxyl (0.03 equiv) was used. e Diethylzinc was used in place of
dimethylzinc.
phenylacetylene 2b with nitroolefin 1a was conducted in the
presence of 1.5 equiv of 3b and 1.5 equiv of dimethylzinc
in toluene at 50 °C for 24 h to give a 64:36 mixture of trans-
and cis-4b with 95% ee and 94% ee, respectively, in 39%
Table 2. Amino Alcohol 3b-Mediated Asymmetric Conjugate
Addition of 2b to Linear Olefins 1b-d Giving 5
(14) Conjugate addition of zinc acetylide: Kim, S.; Lee, J. M. Tetra-
hedron Lett. 1990, 31, 7627-7630.
(15) Conjugate addition of aluminum acetylide: Schwartz, J.; Carr, D.
B.; Hansen, R. T.; Dayrit, F. M. J. Org. Chem. 1980, 45, 3053-3061.
(16) Catalytic asymmetric conjugate addition: (a) Wu, T. R.; Chong, J.
M. J. Am. Chem. Soc. 2005, 127, 3244-3245. (b) Kwak, Y.-S.; Corey, E.
J. Org. Lett. 2004, 6, 3385-3388.
(17) (a) Yamashita, M.; Yamada, K.; Tomioka, K. J. Am. Chem. Soc.
2004, 126, 1945-1946. (b) Yamashita, M.; Yamada, K.; Tomioka, K.
Tetrahedron 2004, 60, 4237-4242.
(18) Our other approaches to asymmetric conjugate addition: (a) Doi,
H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. J. Am. Chem. Soc.
2003, 125, 2886-2887. (b) Kuriyama, M.; Nagai, K.; Yamada, K.; Miwa,
Y.; Taga, T.; Tomioka, K. J. Am. Chem. Soc. 2002, 124, 8932-8939. (c)
Shindo, M.; Koga, K.; Tomioka, K. J. Org. Chem. 1998, 63, 9351-9357.
(d) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 36, 4275-4278. (e)
Shindo, M.; Koga, K.; Tomioka, K. J. Am. Chem. Soc. 1992, 114, 8732-
8733. (f) Tomioka, K.; Shindo, M.; Koga, K. J. Am. Chem. Soc. 1989,
111, 8266-8268.
entry
1
R
temp (°C) time (h) yield (%) ee (%)
1a
2
3
1b n-Bu
1c i-Pr
1d t-Bu
rt
24
72
48
32
44
88
98
96
98
rt
50
a Diethylzinc was used in place of dimethylzinc.
2370
Org. Lett., Vol. 7, No. 12, 2005

Arylacetylenes are the choice of nucleophiles in the present
asymmetric conjugate addition reaction. The reaction of
4-tolyl-, 4-fluorophenyl, 1-naphthyl-, and 3-pyridylacetylenes
2c-f reacted with nitroolefin 1a to give 4c-f with 96-99%
ee in good to moderate yields (Table 3).
Table 3. Amino Alcohol 3b-Mediated Asymmetric Conjugate
Addition of 2b-f to 1a Giving 4b-f
Figure 1. Model 8 predicting the sense of asymmetric induction.
chiral amino alcohol-mediated catalytic asymmetric alkyla-
tion of aldehydes with dialkylzinc reagents (Figure 1). A
zinc metal in the bimetallic complex 8 serves as a Lewis
acid that coordinates to the oxygen of a nitro group, and
then an alkynyl group attacks the double bond to complete
the reaction, giving (R)-4b. The (R)-aboslute configuration
predicted in 8 is identical with that observed.
Not only nitroolefin 1 but also enone is the substrate of
the asymmetic conjugate alkynylation. The reaction of 2b
with chalcone 9 proceeded smoothly at 70 °C for 96 h to
give the conjugate alkynylation product 1016a with 82% ee
in 92% yield (Scheme 2). Thus the present conditions have
entry
2
Ar
temp (°C) time (h) yield (%)a ee (%)b
1
2
3
4
5
2b Ph
2c Tolyl
2d 4-FC6H5
2e 1-Naph
2f 3-Py
rt
30
24
20
48
48
83
85
73
82
30
97
98c
98
99
97
rt
50
rt
50
a Combined yield. The ratio of trans:cis ranges from 73:27 to 21:79 (See
Supporting Information). b Ee (%) of trans-4 unless otherwise mentioned.
c Ee (%) of cis-4c.
Scheme 2. Alkynylation of 9 with 2b
The absolute configuration of 4b was determined to be
(R)- by the conversion to (+)-7 with the established absolute
configuration (Scheme 1).21 The absolute configuration of
other alkynylation products was tentatively assigned as
shown by the reaction analogy.
the possibility of being widely applicable to other types of
activated olefins.
In conclusion, we have developed the highly enantiose-
lective conjugate addition reaction of arylalkyne with nitro-
olefin by the mediation of chiral amino alcohol and
diorganozinc. However, development of a catalytic protocol
and the use of a nonarylalkyne are the targets of the next
stage.
Scheme 1. Determination of the Absolute Configuration of 4b
by Conversion to the Ketone 7 with the Established Absolute
Configuration
Acknowledgment. This research was partially supported
by the 21st Century COE (Center of Excellence) Program
“Knowledge Information Infrastructure for Genome Science”
and a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan.
The sense of asymmetric induction is predictable by the
model 8 originally proposed by Noyori and Oguni22 in the
Supporting Information Available: Reaction procedure
and the characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Rudolph, J.; Hermanns, N.; Bolm, C. J. Org. Chem. 2004, 69, 3997-
4000.
(20) We have reported some radical reactions initiated by dimethylzinc:
(a) Yamamoto, Y.; Maekawa, M.; Yamada, K.; Tomioka, K. Tetrahedron
2005, 61, 379-384. (b) Yamada, K.; Yamamoto, Y.; Tomioka, K. J. Synth.
Org. Chem., Jpn. 2004, 62, 1158-1165. (c) Yamada, K.; Yamamoto, Y.;
Maekawa, M.; Chen, J.; Tomioka, K. Tetrahedron Lett. 2004, 45, 6595-
6597. (d) Yamada, K.; Yamamoto, Y.; Maekawa, M.; Tomioka, K. J. Org.
Chem. 2004, 69, 1531-1534. (e) Yamamoto, Y.; Yamada, K.; Tomioka,
K. Tetrahedron Lett. 2004, 45, 797-799. (f) Yamada, K.; Yamamoto, Y.;
Tomioka, K. Org. Lett. 2003, 5, 1797-1799. (g) Yamada, K.; Fujihara,
H.; Yamamoto, Y.; Miwa, Y.; Taga, T.; Tomioka, K. Org. Lett. 2002, 4,
3509-3511.
OL050643P
(21) Nakamura, M.; Hatakeyama, T.; Hara, K.; Nakamura, E. J. Am.
Chem. Soc. 2003, 125, 6362-6363.
(22) Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.; Oguni,
N.; Hayashi, M.; Kaneko, T.; Matsuda, Y. J. Organomet. Chem. 1990, 382,
19-37.
Org. Lett., Vol. 7, No. 12, 2005
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