Catalytic enantioselective addition of terminal 1,3-diynes to aromatic ketones: Facile access to chiral nonracemic tertiary alcohols

Article abstract of DOI:10.1039/c1cc15968b

An efficient, catalytic, and enantioselective 1,2-addition of terminal 1,3-diynes to aromatic ketones was realized in the presence of 10 mol% of a Cu(OTf)₂-hydroxycamphor-sulfonamide complex, affording chiral tertiary alcohols in up to 94% yiel

Full text of DOI:10.1039/c1cc15968b

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COMMUNICATION
Catalytic enantioselective addition of terminal 1,3-diynes to aromatic
ketones: facile access to chiral nonracemic tertiary alcoholsw
Tian-Lin Liu, Hai Ma, Fa-Guang Zhang, Yan Zheng, Jing Nie and Jun-An Ma*
Received 26th September 2011, Accepted 24th October 2011
DOI: 10.1039/c1cc15968b
An efficient, catalytic, and enantioselective 1,2-addition of terminal
1,3-diynes to aromatic ketones was realized in the presence of
10 mol% of a Cu(OTf)2-hydroxycamphor-sulfonamide complex,
affording chiral tertiary alcohols in up to 94% yield and 90% ee.
and readily available cinchona alkaloids.10 In our initial
attempt to extend this methodology, low reactivity and low
enantioselectivity were observed in the addition of diyne 2a to
acetophenone 1a. Subsequently, the addition of diynylzinc to
acetophenone 1a in the presence of various aminoalcohols also
failed to produce the desired adduct. In comparison with
aldehydes, the attenuated reactivity of ketones means that
strong activators are necessary for reasonable reaction rates.
Next, we decided to employ the Cu-complexes (Chan’s catalyst
system)11 to enhance the reactivity of ketones toward the attack
of diynylzinc (Table 1). We were delighted to find that the
Cu(OTf)2-hydroxycamphorsulfonamide complex was the most
promising catalyst for the test reaction (Table 1, entries 1–5),
whereas the other Cu-complexes tested resulted in lower yields or
enantioselectivities. A series of chiral hydroxycamphor-sulfonamide
derivatives (Fig. 1, I–VI) were screened for the Cu-catalyzed
diynylation of 1a. Ligand II with an endo-hydroxy group gave a
Chiral nonracemic tertiary alcohols are important structural
subunits that can be found in a large number of natural
products, pharmaceuticals, and biologically active compounds.1
The catalytic enantioselective addition of carbon nucleophiles
to prochiral ketones, which can simultaneously construct a
carbon skeleton and tetrasubstituted stereogenic center, represents
the most convergent and efficient approach to the synthesis
of optically active tertiary alcohols.2 Although ketones are
challenging substrates because of their low reactivity and
because of the difficulty in controlling facial stereoselectivity,
many effective methods have been developed for the catalytic
enantioselective C–C bond-forming reactions with ketones. In
this context, the catalytic enantioselective addition of organozinc
to ketones has been extensively studied in the past decade.3
A great effort has been devoted to the development of highly
selective and efficient catalytic systems, and the utilization of
various organozinc reagents including alkyl-,4 aryl-,5 alkenyl-,6
and alkynylzinc7 in this synthetically useful addition transfor-
mation. Despite significant progress made in this area, the use of
terminal 1,3-diynes as carbon nucleophiles in this 1,2-addition
reaction to ketones has been much less investigated.8 Mikami
and coworkers developed an enantioselective palladium-catalyzed
diynylation of ethyl trifluoropyruvate with diynylsilanes.9
Although the yields as well as the enantioselectivities are good
to high, the main drawback is the use of the limited ketone
substrate. As a result of efforts toward the development of new
catalytic reactions with challenging substrates, herein we report the
first general, facile, and effective method for the catalytic enantio-
selective addition of terminal 1,3-diynes to aromatic ketones.
Such studies would be of immense benefit for expanding the scope
of application of this addition reaction in organic synthesis.
We recently developed a catalytic enantioselective alkynylation
of trifluoromethyl ketones by a combination of Ti(OPri)4, BaF2,
Table 1 Optimizing of conditions for the addition of 2a to 1a to give 3aa
Entry Catalyst (mol%) Solvent Temp/1C Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
Cu(OTf)2/I (10)
CuF2/I (10)
CuOTf/I (10)
CuI/I (10)
DCM
DCM
DCM
DCM
DCM
25
25
25
25
25
25
25
25
25
25
25
25
94
67
90
10
73
52
95
90
82
45
90
20
90
92
0
70
14
68
—
20
10
75
50
22
13
75
15
60
57
0
CuBr/I (10)
Cu(OTf)2/II (10) DCM
Cu(OTf)2/III (10) DCM
Cu(OTf)2/IV (10) DCM
Cu(OTf)2/V (10) DCM
Cu(OTf)2/VI (10) DCM
Cu(OTf)2/III (10) DCE
Cu(OTf)2/III (10) CHCl3
9
10
11d
12
13
14
15
16
17
18
19
20
Cu(OTf)2/III (10) Toluene 25
Cu(OTf)2/III (10) Benzene 25
Cu(OTf)2/III (10) Et2O
Cu(OTf)2/III (10) THF
Cu(OTf)2/III (10) DCM
Cu(OTf)2/III (10) DCM
Cu(OTf)2/III (15) DCM
Cu(OTf)2/III (5) DCM
25
25
10
0
10
10
0
0
94
88
95
60
77
77
75
60
Department of Chemistry, Tianjin University, Tianjin 300072, China.
E-mail: majun_an68@tju.edu.cn; Fax: +86-22-2740-3475
w Electronic supplementary information (ESI) available. CCDC
830329. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1cc15968b
a
Acetophenone : buta-1,3-diynylbenzene : Me2Zn = 1 : 2.6 : 3 (equivalent
b
ratio) for 48 h. Isolated yield. Enantiomeric excess was determined by
d
chiral HPLC analysis. DCE: dichloroethane.
c
c
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Table 2 Scope of the catalytic enantioselective 1,2-addition of terminal
1,3-diynes to aromatic ketones to afford product 3a
Entry
1
Product
Yieldb (%)
eec (%)
94
77
Fig. 1 Chiral ligands tested in the addition reaction of diynes to
ketones.
2
3
4
5
6
92
91
88
60
67
90
90
79
71
71
very poor ee (entry 6). The modification of the methylamine
moiety with bulky aryl groups gave rise to the fluctuation in
enantioselectivity (entries 7–10), with 10 mol% of ligand III
giving the best performance in terms of both the yield and the
enantioselectivity (entry 7). A comparison of the results obtained
in different solvents showed that this asymmetric transformation
is highly sensitive to the solvent used (entries 11–16). No reaction
occurred in the coordinating solvents, and dichloromethane
(DCM) was found to be the best solvent for this reaction.
Further optimization by changing the temperature and the
catalyst loading (entries 17–20) led to the discovery that the best
results were obtained when 10 mol% of the Cu(OTf)2-III
complex was used at 10 1C (94% yield, 77% ee, entry 17).
With the optimized reaction conditions in hand, we explored
the scope of this diynylation reaction by varying the aromatic
ketones and the terminal 1,3-diynes. The results are summarized
in Table 2. Most of the tertiary diynols were obtained in good
chemical yields, yet the ee values were dependent on the
nucleophilic property of the diyne and the steric hindrance
of the ketone substrate. For all aromatic ketones studied
that bear substituents in the 2-, 3-, or 4-position, the enantio-
meric excess of the tertiary diynols 3a–k was in the range
of 65–90% (entries 1–11). Aromatic ketones that contain
an electron-donating group reacted slowly with terminal 1,3-
diyne. For example, 20- and 40-methylacetophenones gave the
desired products in the yield of 60% and 67%, respectively
(entries 5 and 6). Additionally, the reaction worked well with
1-(naphthalen-2-yl)ethanone to afford the 1,2-adduct 3l in
good yield and enantioselectivity (entry 12). Propiophenone
gave the corresponding product 3m in 95% yield with 62% ee
(entry 13). Further exploration of the substrate scope focused
on the nucleophilic diynes. It appeared that electron-donating
and electron-withdrawing substituents on the aromatic ring can
be tolerated, and good stereocontrol (62–80% ee) was observed
for the products 3n–r (entries 14–18). Alicyclic diyne also
gave the diynylation adduct 3s in good yield and enantio-
selectivity (entry 19). Triisopropylsilyl-substituted 1,3-diyne is
also a viable substrate, affording the desired product 3t in 70%
yield with 72% ee (entry 20). In addition, we investigated the
addition reaction with 2-butanone, 3,3-dimethyl-2-butanone,
and (4-chlorophenyl)(phenyl)methanone. These substrates were
found to be unsuitable for this asymmetric transformation and
poor enantioselectivity (o15%) was observed.
7
8
9
83
86
80
71
72
65
10
11
12
13
95
92
71
91
81
70
68
62
To evaluate this catalytic system on a large-scale, 3 mmol
of substrate 1c was used to perform the diynylation addition
c
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12874 Chem. Commun., 2011, 47, 12873–12875

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Table 2 (continued )
the Si-face of the ketone was predominantly approached by
the nucleophilic diyne.
Entry
Product
Yieldb (%)
eec (%)
In summary, we have successfully developed the first catalytic
enantioselective addition of terminal 1,3-diynes to aromatic
ketones. In the presence of chiral hydroxycamphorsulfonamide,
the reaction proceeded smoothly to afford a series of chiral
tertiary alcohols in 60–94% yield with 62–90% ee. Further
mechanistic investigation, extension of the reaction scope, and
additional improvement on the enantioselectivity are ongoing in
our laboratory.
14
90
80
15
16
82
77
70
62
This work was supported financially by NSFC (No. 20972110
and 20902067).
Notes and references
1 C. Garcia and V. S. Martin, Curr. Org. Chem., 2006, 10, 1849.
2 Selected reviews: (a) Quaternary Stereocentres: Challenges and
Solutions for Organic Synthesis, ed. J. Christoffers and A. Baro,
Wiley-VCH, 2005; (b) O. Riant and J. Hannedouche, Org. Biomol.
Chem., 2007, 5, 873; (c) M. Shibasaki and M. Kanai, Chem. Rev.,
2008, 108, 2853; (d) J. P. Das and I. Marek, Chem. Commun., 2011,
47, 4593.
17
18
19
79
85
66
67
3 Selected reviews, see: (a) M. Yus and D. J. Ramo
Dev. Org. Chem., 2002, 6, 297; (b) D. J. Ramon and M. Yus,
Angew. Chem., Int. Ed., 2004, 43, 284.
´
n, Recent Res.
´
4 Selected reviews, see: (a) L. Pu and H.-B. Yu, Chem. Rev., 2001,
101, 757; (b) M. M. Hussain and P. J. Walsh, Acc. Chem. Res.,
2008, 41, 883; (c) B. M. Trost, T. Zhang and J. D. Sieber, Chem.
Sci., 2010, 1, 427; and references therein.
85
71
79
72
´
5 For a review, see: J. M. Betancort, C. Garcıa and P. J. Walsh,
Synlett, 2004, 749; and references therein.
6 (a) H. Li and P. J. Walsh, J. Am. Chem. Soc., 2004, 126, 6538;
(b) H. Li and P. J. Walsh, J. Am. Chem. Soc., 2005, 127, 8355.
7 For selected reviews, see: (a) L. Pu, Tetrahedron, 2003, 59, 9873;
(b) G. Lu, Y.-M. Li, X.-S. Li and A. S. C. Chan, Coord. Chem.
Rev., 2005, 249, 1736; (c) L. Lin and R. Wang, Curr. Org. Chem.,
2009, 13, 1565; (d) B. M. Trost and A. H. Weiss, Adv. Synth.
Catal., 2009, 351, 963, and selected examples, see: (e) B. Jiang,
Z. Chen and X. Tang, Org. Lett., 2002, 4, 3451; (f) P. G. Cozzi,
Angew. Chem., Int. Ed., 2003, 42, 2895; (g) B. Saito and T. Katsuki,
Synlett, 2004, 1557; (h) P. G. Cozzi and S. Alesi, Chem. Commun.,
2004, 2448; (i) Y. Zhou, R. Wang, Z. Xu, W. Yan, L. Liu, Y. Kang
20
a
The reaction was run with 10 mol% Cu(OTf)2/III at 10 1C for 48 h.
Isolated yield. ee was determined by HPLC analysis using a chiral
stationary phase.
b
c
and the product 3c was obtained in 95% yield and 90% ee.
Further transformation of the adduct 3c furnished the crystal-
line derivative 4 whose absolute stereochemistry was deter-
mined to be S from single-crystal X-ray structural analysis
(Scheme 1).12 Thus, we established that the absolute configu-
ration of the major enantiomer 3c is S. These results show that
and Z. Han, Org. Lett., 2004, 6, 4147; (j) V. J. Forrat, D. J. Ramon
´
and M. Yus, Tetrahedron: Asymmetry, 2005, 16, 3341; (k) L. Liu,
R. Wang, Y.-F. Kang, H.-Q. Cai and C. Chen, Synlett, 2006, 1245;
(l) C. Chen, L. Hong, Z.-Q. Xu, L. Liu and R. Wang, Org. Lett.,
2006, 8, 2277; (m) V. J. Forrat, O. Prieto, D. J. Ramon and
´
M. Yus, Chem.–Eur. J., 2006, 12, 4431; (n) Q. Wang, B. Zhang,
G. Hu, C. Chen, Q. Zhao and R. Wang, Org. Biomol. Chem.,
2007, 5, 1161; (o) C. Chen, L. Hong, B. Zhang and R. Wang,
Tetrahedron: Asymmetry, 2008, 19, 191; (p) R. Motoki, M. Kanai
and M. Shibasaki, Org. Lett., 2007, 9, 2997; (q) T. Ohshima,
T. Kawabata, Y. Takeuchi, T. Kakinuma, T. Iwasaki,
T. Yonezawa, H. Murakami, H. Nishiyama and K. Mashima,
Angew. Chem., Int. Ed., 2011, 50, 6296.
8 Four reports on the enantioselective diynylation of aldehydes, see:
(a) S. Reber, T. F. Knopfel and E. M. Carreira, Tetrahedron, 2003,
¨
59, 6813; (b) B. M. Trost, V. S. Chan and D. Yamamoto, J. Am.
Chem. Soc., 2010, 132, 5186; (c) M. Turlington, Y. Du,
S. G. Ostrum, V. Santosh, K. Wren, T. Lin, M. Sabat and
L. Pu, J. Am. Chem. Soc., 2011, 133, 11780; (d) E. R. Graham
and R. R. Tykwinski, J. Org. Chem., 2011, 76, 6574.
9 K. Aikawa, Y. Hioki and K. Mikami, Org. Lett., 2010, 12, 5716.
10 G.-W. Zhang, W. Meng, H. Ma, J. Nie, W.-Q. Zhang and
J.-A. Ma, Angew. Chem., Int. Ed., 2011, 50, 3538.
11 (a) G. Lu, X. Li, X. Jia, W. L. Chan and A. S. C. Chan, Angew.
Chem., Int. Ed., 2003, 42, 5057; (b) G. Lu, X. Li, Y.-M. Li,
F. Y. Kwong and A. S. C. Chan, Adv. Synth. Catal., 2006,
348, 1926.
12 The absolute configuration of 4 was confirmed by X-ray crystal
structure analysis. See ESIw for further details. Crystallographic
data for 4: CCDC 830329.
Scheme 1 Scaled-up version of the addition reaction, further trans-
formation, and X-ray structure for the determination of the absolute
configuration.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12873–12875 12875