Studies into asymmetric catalysis of the Nozaki-Hiyama allenylation

Article abstract of DOI:10.1002/anie.200502871

(Chemical Equation Presented) From aldehydes to allenic alcohols: Studies into the asymmetric catalysis of the Nozaki-Hiyama allenylation are described. Ligand 1a is effective for the enantioselective allenylations of various aldehydes, with the generatio

Full text of DOI:10.1002/anie.200502871

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in terms of efficiency; however, most of the asymmetric
catalysis of allenylation reported so far requires preparation
of propargyltin or propargylsilane compounds in advance,
thereby rendering the asymmetric catalysis of allenylation
inconvenient.
On the other hand, allenylations with low-valent metals
and propargyl halides are advantageous with regard to their
ease of manipulation; thus, the required operation is just
mixing the commercially available reagents.[6a] The allenyl-
ation with CrII and a propargyl halide is particularly useful
due to its easy operation, high chemoselectivity, and excellent
compatibility with various functional groups; hence, this
method has been developed by some research groups.[10]
We have reported highly enantioselective Nozaki–
Hiyama allylations[11] and propargylations[12a] by utilizing a
new carbazole tridentate ligand and have shown the wide
applicability of this ligand (Scheme 1). Since no enantiose-
Asymmetric Catalysis
DOI: 10.1002/anie.200502871
Studies into Asymmetric Catalysis of the
Nozaki–Hiyama Allenylation**
Masahiro Inoue and Masahisa Nakada*
The allene moiety represents a versatile and useful functional
group in organic synthesis because of its unique reactivity.[1]
Recent developments in the chemistry of allenes suggest that
allenic alcohols are important synthetic intermediates
because they can be stereoselectively converted into com-
pounds with other functional groups, for example, the amino
alcohols[2] and 2,5-dihydrofurans,[1a,3] and they can also be
used as substrates for Pauson–Khand reactions[1a,4] and Pd-
mediated reactions.[1a,5]
Allenic alcohols are generally prepared by allenylation of
carbonyl compounds,[1b,e,6] and chiral ones have been elabo-
rated by asymmetric synthesis.[1a,7,8] Among the enantioselec-
tive methods, catalytic asymmetric synthesis[1a,9] is important
Scheme 1. Asymmetric catalysis of the Nozaki–Hiyama allylation,
methallylation, and propargylation. DIPEA=diisopropylethylamine,
TMS=trimethylsilyl, TBAF=tetrabutylammonium fluoride, DME=1,2-
dimethoxyethane.
lective allenylation with a low-valent metal and propargyl
halide has been reported, we have examined the asymmetric
catalysis of the Nozaki–Hiyama allenylation, and we report
herein the first successful results.
[*] M. Inoue, Prof. M. Nakada
Department of Chemistry
It has been shown that an equilibrium between the
allenylchromium(iii) and propargylchromium(iii) intermedi-
ates exists in the reaction with CrII and a propargylic halide
and that the ratio of these intermediates depends on their
structure and/or additives.[10b,12–14] Consequently, these inter-
mediates deliver the homopropargylic alcohol and the allenic
alcohol, respectively.
Faculty of Science and Engineering
Waseda University
3-4-1, Ohkubo, Shinjuku, Tokyo 169-8555 (Japan)
Fax: (+81)3-5286-3240
E-mail: mnakada@waseda.jp
[**] This work was financially supported in part by a Waseda University
Grant for Special Research Projects, a Grant-in-Aid for Scientific
Research on Priority Areas “Creation of Biologically Functional
Molecules” (Grant no.: 17035082), and a Grant-in-Aid for Scientific
Research (C) from the Ministry of Education, Culture, Sports,
Science, and Technology (MEXT), Japan. We are also indebted to
21COE “Practical Nano-Chemistry”.
Allenylations of carbonyl compounds with CrII and the
terminally substituted propargyl halides afford allenic alco-
hols as the major products;[10b,12–14] hence, we surmised that
the terminally silylated propargyl halide would generate the
2-silylated secondary allenic alcohol,[15] which can be easily
desilylated[8c] and can also be used as the allenylsilane.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Asymmetric catalysis of the Nozaki–Hiyama allenylation of ben-
zaldehyde.
Therefore, we focused our attention on the study of the
asymmetric catalysis of the Nozaki–Hiyama allenylation with
terminally silylated propargyl halides.
First, a CrII-mediated reaction of commercially available
1-trimethylsilyl-3-bromopropyne[16] with benzaldehyde in the
absence of the chiral ligand under catalytic conditions[11,13a]
was carried out (Scheme 2). The reaction was complete after
4 h and afforded the allenic alcohol as the sole product in
85% yield.
Entry Ligand Solvent T [8C] Base[a]
R3Si[b] t [h] Yield [%] ee [%][c]
1
2
3
1a
1b
1c
THF
THF
THF
THF
DME
CH3CN RT
EtCN RT
CH2Cl2 RT
DMF
EtCN
EtCN
EtCN
EtCN
RT
RT
RT
RT
RT
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
K2CO3
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
6
8
90
92
64
52
12 92
85
À29[d]
4[e] 1a
8
47
61
60
71
5
6
7
8
9
1a
1a
1a
1a
1a
1a
12 72
12 74
12 83
24 49
48 56[f]
16 80
20 81
16 72
16 65
57
RT
0
0
0
0
74[g]
76
Scheme 2. The catalytic Nozaki–Hiyama allenylation without ligand.
10
11[h] 1a
76
76
76
Consequently, a CrII/chiral-ligand-mediated reaction of 1-
trimethylsilyl-3-bromopropyne with benzaldehyde was car-
ried out. This catalytic asymmetric allenylation followed the
same procedure as that used for the catalytic asymmetric
allylation and propargylation.[11]
The reaction with ligand 1a was complete after 6 h and
generated the R product in 90% yield with 64% ee (Table 1,
entry 1).[17] The reaction with 1b took 8 h to finish and
generated the R product in 92% yield with 52% ee (entry 2).
Interestingly, the enantioselectivity in the reaction with 1c
was reversed to afford the S product in 92% yield with 29%
ee after 12h. [18] It is noteworthy that the least bulky ligand 1a
gave the best result and only allenic alcohols were generated
in all the reactions described in entries 1–3. The reaction with
the propargyl chloride and 1a did not improve the result
(entry 4; 85%, 47% ee).
Next, the reaction was carried out in various solvents by
using the most effective ligand, that is, 1a, and propargyl
bromide. The reactions in DME (entry 5) and acetonitrile
(entry 6) required 12h for completion and the ee values were
slightly decreased. Although the reaction time was not
shortened, propionitrile increased the ee value to 71%
(entry 7). Other solvents gave fruitless results; for example,
the reaction in CH2Cl2 required much more time and both the
yield and the ee value were decreased (entry 8; 24 h, 49%,
57% ee). DMF generated the allenic alcohol (36%, 74% ee)
along with the propargylic alcohol (20%, 4% ee).
The reaction at 08C delayed the reaction time (16 h);
however, the ee value was increased to 76% (entry 10).
Hence, all the reactions were carried out at 08C after this. Use
of molecular sieves did not affect the ee value and merely
prolonged the reaction time (entry 11).
12
13
1a
1a
g-colli- TMS
dine
14
15
16
17
18
19
1a
1a
1a
1a
1a
1a
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
0
0
0
0
0
0
pyridine TMS
30 64
24 81
30 49
65
74
66
73
73
80
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
TES
TIPS
DMPS 24 66
MDPS 30 79
DMS 16 81
[a] 30 mol% was used. [b] TES=triethylsilyl, TIPS=triisopropylsilyl,
DMPS=dimethylphenylsilyl, MDPS=methyldiphenylsilyl. [c] The ee value
as determined by HPLC. [d] The minus sign indicates that the enantiose-
lectivity of the reaction was reversed in this case to afford the S product.
[e] 1-trimethylsilyl-3-chloropropyne was used instead of 1-trimethylsilyl-3-
bromopropyne. [f] A mixture of allenic alcohol and homopropargylic alcohol
(1.8:1) was obtained and the combined yield is given. [g] The ee value of the
allenic alcohol as determined from the corresponding a-methoxy-a-
(trifluoromethyl)phenylacetyl (MTPA) ester. The ee value of the homopro-
pargylic alcohol was 4%. [h] 4 Š molecular sieves (200 wt%) were added.
bulkier than the TMS group (TES, TIPS, DMPS, and MDPS)
did not improve the enantioselectivity (entries 15–18), the
smaller DMS group (entry 19) afforded the best result (81%,
80% ee).
As noted above, when DMF was the solvent (Table 1,
entry 9), the ee value of the allenic alcohol was high (74% ee).
Consequently, the reaction in the presence of an additive
possessing a polar functional group was examined. The
additives possessing an oxygen–phosphine bond (Table 2,
entries 1–4) or oxygen–sulfur bond (entry 5) had no effect on
the enantioselectivity; however, some ureas improved the ee
value. Thus, the reaction in the presence of DMPU afforded
the product in 91% yield with 82% ee (entry 6), and the
reaction in the presence of DMI gave the best enantioselec-
tivity (entry 7; 97%, 83% ee). Other ureas (entries 8–11) did
not improve upon the result given in entry 7.
Under the optimized conditions (Table 2, entry 7), various
aldehydes were successfully allenylated with high enantiose-
lectivity. p-Methoxybenzaldehyde and p-chlorobenzaldehyde
were allenylated in 90% yield with 80% ee (Table 3, entry 1)
and in 91% yield with 82% ee (entry 2), respectively.
Hydrocinnamaldehyde (entry 3; 99%, 72% ee), cyclohexyl-
The base used to prepare the chiral catalyst was also
surveyed.[11b] Potassium carbonate (entry 12) and bulky g-
collidine (entry 13), which would not coordinate to chro-
mium, gave results comparable with those obtained by the use
of DIPEA; however, pyridine (entry 12) gave diminished
results in all respects (reaction time, yield, and ee value),
probably due to its strongly coordinating nature.
We found that the silyl group of the propargyl halide
affected the enantioselectivity; that is, while silyl groups
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Table 2: Effect of additive on the catalytic asymmetric Nozaki–Hiyama
allenylation of benzaldehyde.
Figure 1. Proposed model for the catalytic asymmetric Nozaki–Hiyama
allenylation. DMS=dimethylsilyl.
Entry
Additive[a] (1 equiv)
t [h]
Yield [%]
ee[b] [%]
1
2
3
4
5
6
7
8
9
HMPA
Ph3P(O)
nBu3P(O)
(PhO)3P(O)
DMSO
DMPU
DMI
24
24
36
48
30
24
24
36
48
36
16
75
69
23
20
73
91
97
76
80
77
55
79
82
83
73
67
75
81
position of the asymmetric catalyst, the aldehyde coordinated
at the equatorial position and was allenylated from the si face
under the influence of the asymmetric circumstances.
However, several other explanations for the enantiose-
lectivity are possible. For example, the possibilities of the
reaction proceeding intermolecularly or the Cr–1 complex
being a dinuclear complex[20] cannot be ruled out. Further-
more, the stereochemical outcome of this allenylation reac-
tion could derive from different chromium complexes. Hence,
further studies on the structure of the Cr–1a complex and the
mechanism of this reaction are in progress.
The product obtained through this asymmetric catalysis
would be a good synthetic intermediate because the silyl
group can be easily desilylated.[8c] For example, as shown in
Scheme 3, the allenylated product 2 was easily desilylated to
afford 3 in 100% yield without diminishing the ee value.
DMI[c]
17[d]
21[e]
71
TMU
DEDPU
DTBI
10
11
73
[a] HMPA=hexamethyl phosphoramide, DMSO=dimethylsulfoxide,
DMPU=N,N’-dimethylpropylene urea, DMI=1,3-dimethyl-2-imidazoli-
dinone, TMU=N,N,N’,N’-tetramethylurea, DEDPU=N,N’-diethyl-N,N’-
diphenylurea, DTBI=1,3-di-tert-butyl-2-imidazolidinone. [b] The ee value
as determined by HPLC. [c] 10 equivalents of DMI were used. [d] A large
amount of pinacol coupling product was formed (52% yield). [e] Homo-
propargylic alcohol was identified by 1HNMR spectroscopy; the ratio of
products was allenic alcohol:homopropargylic alcohol=50:1.
Table 3: Asymmetric catalysis of the Nozaki–Hiyama allenylation of
various aldehydes.
Scheme 3. Desilylation of the products.
In summary, ligand 1a was found to realize the catalytic
asymmetric allenylation of various aldehydes with high
enantioselectivity. To the best of our knowledge, this is the
first successful example of the asymmetric catalysis of the
Nozaki–Hiyama allenylation. The product obtained from this
reaction would be a useful synthetic intermediate because the
2-silylated secondary allenic alcohol can be easily desilylated
or can be used as the allenylsilane; hence, we will investigate
the utility of this allenic alcohol for the total synthesis of
natural products.
Entry
R
t [h]
Yield [%]
ee[a] [%]
1
2
3
4
5
p-MeOPh
p-ClPh
PhCH2CH2
c-C6H11
36
24
24
24
24
90
91
99
95
81
80
82
72
74
75
n-C5H11
[a] The ee value as determined by HPLC.
aldehyde (entry 4; 95%, 74% ee), and pentanal (entry 5;
81%, 75% ee) were also allenylated with good enantioselec-
tivity, thereby revealing the generality of this catalytic
asymmetric allenylation.
Received: August 12, 2005
Published online: November 30, 2005
Keywords: allenes · allenic alcohols · asymmetric catalysis ·
The absolute configurations of the products were deter-
mined by comparing the sign of the specific rotation with
known compounds;[19] this disclosed that all the aldehydes
showed the same enantioface selectivity. Thus, all the
aldehydes were allenylated predominantly at the si face.
Compared with the previously reported catalytic asym-
metric propargylation,[12a] in which the aldehydes showed re-
face selectivity (Scheme 1), the enantioface selectivity in the
allenylation is reversed. This reversal is well explained, as
shown in Figure 1. Thus, since the terminally silylated
propargyl group was positioned at the less-hindered apical
.
chromium · enantioselectivity
[1] a) Modern Allene Chemistry (Eds.: N. Krause, A. S. K. Hashmi),
Wiley-VCH, Weinheim, 2004; b) N. Krause, A. Hoffmann-
Röder, Tetrahedron 2004, 60, 11671 – 11694; A. Barbero, F. J.
Pulido, Acc. Chem. Res. 2004, 37, 817 – 825; c) A. Barbero, F. J.
Pulido, Synthesis 2004, 779 – 785; d) S. Ma, Acc. Chem. Res. 2003,
36, 701 – 712; e) H. Yamamoto in Comprehensive Organic
Synthesis, Vol. 2 (Eds.: B. M. Trost, I. Fleming), Pergamon,
Oxford, 1991, Chap. 1.3, pp. 81 – 131.
254
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Chemie
[2] R. W. Friesen, Tetrahedron Lett. 1990, 31, 4249 – 4252.
[3] a) N. Krause, A. Hoffmann-Röder, J. Canisius, Synthesis 2002,
1759 – 1774; b) A. Hoffmann-Röder, N. Krause, Org. Lett. 2001,
3, 2537 – 2538; c) L. I. Olsson, A. Claesson, Synthesis 1979, 9,
743 – 745.
[4] a) C. Mukai, I. Nomura, S. Kitagaki, J. Org. Chem. 2003, 68,
1376 – 1385; b) B. Alcaide, P. Almendros, C. Aragoncillo, Chem.
Eur. J. 2002, 8, 1719 – 1729.
[5] a) D. Xu, Y. Xu, L. Li, S. Ma, Chem. Eur. J. 2002, 8, 5012– 5018;
b) S. Ma, S. Zhao, J. Am. Chem. Soc. 2001, 123, 5578 – 5579; c) S.
Ma, W. Gao, Tetrahedron Lett. 2000, 41, 8933 – 8936; d) S. Ma, S.
Zhao, J. Am. Chem. Soc. 1999, 121, 7943 – 7944; e) S.-K. Kang, T.
Yamaguchi, S.-J. Pyun, Y.-T. Lee, T.-G. Baik, Tetrahedron Lett.
1998, 39, 2127 – 2130.
[6] a) M.-J. Lin, T.-P. Loh, J. Am. Chem. Soc. 2003, 125, 13042–
13043; b) T. Nishikawa, H. Shinokubo, K. Oshima, Tetrahedron
2003, 59, 9661 – 9668; c) T. Hamada, R. Mizojiri, H. Urabe, F.
Sato, J. Am. Chem. Soc. 2000, 122, 7138 – 7139; d) S. Kobayashi,
K. Nishio, J. Am. Chem. Soc. 1995, 117, 6392– 6393.
[7] For a review, see: S. E. Denmark, J. Fu, Chem. Rev. 2003, 103,
2763 – 2793.
[19] (S)-1-phenyl-2,3-butadien-1-ol: [a]2D6 = + 28.7 (c = 0.72, CHCl3)
(R form:[19a] [a]2D0 = À55.4 (c = 0.82, CHCl3)); (R)-1-phenyl-2,3-
hexadien-1-ol: [a]2D6 = + 3.04 (c = 0.77, CHCl3) (S form:[19b]
[a]2D3 = À2.4 (c = 1.41, CHCl3)); (R)-1,2-nonadien-4-ol: [a]2D6
=
À5.00 (c = 0.73, CHCl3) (S form:[19c] [a]D23 = + 4.5 (c = 0.2,
CHCl3)); (R)-1-cyclohexyl-2,3-butadien-1-ol: [a]2D6 = À7.7 (c =
0.40, benzene) (S form:[19b] [a]2D4 = + 10.5 (c = 1.02, benzene));
a) C.-M. Yu, C. Kim, J.-H. Kweon, Chem. Commun. 2004, 2494 –
2495; b) K. Iseki, Y. Kuroki, Y. Kobayashi, Tetrahedron:
Asymmetry 1998, 9, 2889 – 2894; c) E. J. Corey, G. B. Jones,
Tetrahedron Lett. 1991, 32, 5713 – 5716. With regard to the
products of p-methoxybenzaldehyde and p-chlorobenzaldehyde,
the absolute configurations were determined by analogy because
these products showed the same sign (minus) as that of the
product of benzaldehyde.
[20] For example, see: R. Ruck, E. N. Jacobsen, J. Am. Chem. Soc.
2002, 124, 2882 – 2883.
[8] a) C. Schultz-Fademrecht, B. Wibbeling, R. Froehlich, D. Hoppe,
Org. Lett. 2001, 3, 1221 – 1224; b) A. Marshall, N. D. Adams, J.
Org. Chem. 1997, 62, 8976 – 8977; c) H. C. Brown, U. R. Khire,
G. Narla, J. Org. Chem. 1995, 60, 8130 – 8131; d) E. J. Corey,
G. B. Jones, Tetrahedron Lett. 1991, 32, 5713 – 5716.
[9] a) M. Nakajima, M. Saito, S. Hashimoto, Tetrahedron: Asym-
metry 2002, 13, 2449 – 2452; b) K. Iseki, Y. Kuroki, Y. Kobayashi,
Tetrahedron: Asymmetry 1998, 9, 2889 – 2894; c) C.-M. Yu, S.-K.
Yoon, K. Baek, J.-Y. Lee, Angew. Chem. 1998, 110, 2504 – 2506;
Angew. Chem. Int. Ed. 1998, 37, 2392 – 2395.
[10] a) P. Knochel, J. Org. Chem. 1992, 57, 4070 – 4074; b) J. Gore,
Tetrahedron 1981, 37, 1359 – 1367.
[11] a) M. Inoue, T. Suzuki, M. Nakada, J. Am. Chem. Soc. 2003, 125,
1140 – 1141; b) T. Suzuki, A. Kinoshita, H. Kawada, M. Nakada,
Synlett 2003, 570 – 572.
[12] a) M. Inoue, M. Nakada, Org. Lett. 2004, 6, 2977 – 2980. We
obtained an allenyl alcohol as a minor product in the catalytic
asymmetric propargylation under certain conditions. The same
result had been obtained by Umani-Ronchiꢀs group; see: b) M.
Bandini, P. G. Cozzi, P. Melchiorre, R. Tino, A. Umani-Ronchi,
Tetrahedron: Asymmetry 2001, 12, 1063 – 1069.
[13] For recent progress in chromium-mediated reactions, see: a) A.
Fꢁrstner, Chem. Rev. 1999, 99, 991 – 1045; b) L. A. Wessjohann,
G. Scheid, Synthesis 1991, 1 – 36.
[14] a) P. Wipf, S. Lim, J. Chem. Soc. Chem. Commun. 1993, 1654 –
1656; b) K. Belyk, M. J. Rozema, P. Knochel, J. Org. Chem. 1992,
57, 4070 – 4074; c) B. Le Doussal, A. Le Coq, A. Gorgues, A.
Meyer, Tetrahedron 1983, 39, 2185 – 2192; d) T. Hiyama, Y.
Okude, K. Kimura, H. Nozaki, Bull. Chem. Soc. Jpn. 1982, 55,
561 – 568; e) B. Cazes, C. Verniꢂre, J. Gorꢂ, Tetrahedron Lett.
1982, 23, 3501 – 3504; f) P. Place, F. Delbecq, J. Gorꢂ, Tetrahe-
dron Lett. 1978, 3801 – 3802.
[15] To the best of our knowledge, this is the first example of the use
of the terminally silylated propargylic halide for the regioselec-
tive allenylation.
[16] H. D. Verkruijsse, L. Brandsma, Synth. Commun. 1990, 20,
3375 – 3378.
[17] The allenylation of benzaldehyde with 1-bromo-2-butyne was
examined under the same conditions as those described in
entry 1 of Table 1; however, a mixture of the allenic alcohol and
the homopropargylic alcohol was obtained in a ratio of 2.7:1 in
90% combined yield, and the ee values were 22 and 14%,
respectively.
[18] This change of enantioselectivity has also been observed in the
catalytic asymmetric propargylation. For the results and the
proposed explanation, see reference [12a].
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