Catalytic asymmetric aldol-type reaction of zinc enolate equivalent of amides

Article abstract of DOI:10.1021/ol401425s

Treatment of phenyl isocyanate with bis(iodozincio)methane gave a zinciomethylenated product, which acts as an amide-enoate equivalent. It did not react with an aldehyde efficiently, but gave the corresponding adduct in good yield in the presence of an aminoalcohol. Use of a catalytic amount of chiral aminoalcohol led the process to the catalytic asymmetric Aldol-type reaction.

Full text of DOI:10.1021/ol401425s

ORGANIC
LETTERS
2013
Vol. 15, No. 13
3378–3380
Catalytic Asymmetric Aldol-Type Reaction
of Zinc Enolate Equivalent of Amides
Ryosuke Haraguchi and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyotodaigaku-katsura, Nishikyo, Kyoto 615-8510, Japan
matsubara.seijiro.2e@kyoto-u.ac.jp
Received May 20, 2013
ABSTRACT
Treatment of phenyl isocyanate with bis(iodozincio)methane gave a zinciomethylenated product, which acts as an amide-enoate equivalent. It did
not react with an aldehyde efficiently, but gave the corresponding adduct in good yield in the presence of an aminoalcohol. Use of a catalytic
amount of chiral aminoalcohol led the process to the catalytic asymmetric Aldol-type reaction.
Organozinc reagents are considered one of the most
important main-metal reagents because of their compat-
ibility with many functional groups.1 An organic reagent
carrying various functional groups has been developed;
it can be used, through a CÀC bond formation reaction, to
directly introduce functional groups to a substrate.2 During
the course of our studies on bis(iodozincio)methane (1)
prepared by the reduction of diiodomethane with zinc,
we have shown several examples of zinciomethylenation,
which involve the direct introduction of a CÀZn bond.3 The
reaction of bis(iodozincio)methane with an acylating reagent
affords an R-zinciocarbonyl, which is an enolate. We have
already reported the palladium-catalyzed cross coupling of 1
with a thioester to afford the corresponding zinc enolate of
ketone.4 Along this line, we focused on the insertion reaction
of the CÀZn bond of 1 into a heterocumulene as an
alternative for enolate equivalent preparation.
The zinciomethylation ofanisocyanate with1 affords an
equivalent of an amide enolate. As shown in Scheme 1,
phenylisocyanate (2) was treated with an equimolar amount
of dizinc 1. An addition would afford three possible types
of adducts 3aÀc. To complete the addition reaction in THF
or toluene within 0.5 h, it was necessary for the reaction of
1 and 2 to be performed at 80 °C, as shown in Table 1.
(1) (a) Knochel, P.; Perea, J. J. A.; Jones, P. Tetrahedorn 1998, 54,
8275. (b) Knochel, P.; Scade, M. A.; Bernhardt, S.; Manolikakes, G.;
Metzger, A.; Piller, F. M.; Rohbogner, C. J.; Mosrin, M. Beil. J. Org.
Chem. 2011, 7, 1261.
Scheme 1. An Addition of Bis(iodozincio)methane with Phenyl
Isocyanate
(2) Knochel, P.; Leuser, H.; Gong, L.-Z.; Perrone, S.; Kneisel, F. F.
Functionalized Organozinc Compounds. In The Chemistry of Organo-
zinc Compounds Part 1; Rappoport, Z.; Marek, I., Eds.; John Wiley & Sons:
West Sussex, England; 2006; pp 287À393.
(3) (a) Ikeda, Z.; Oshima, K.; Matsubara, S. Org. Lett. 2005, 7, 4859.
(b) Hirayama, T.; Oshima, K.; Matsubara, S. Angew. Chem., Int. Ed.
2005, 44, 3293. (c) Utimoto, K.; Toda, N.; Mizuno, T.; Kobata, M.;
Matsubara, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2804.
(4) (a) Ikeda, Z.; Hirayama, T.; Matsubara, S. Angew. Chem., Int. Ed.
2006, 45, 8200. (b) Ooguri, A.; Ikeda, Z.; Matsubara, S. Chem. Commun.
2007, 4761. (c) Matsubara, S.; Kawamoto, K.; Utimoto, K. Synlett 1998,
267.
AsshowninScheme 2, the addition of benzaldehyde (5a)
to 3 afforded the corresponding aldol-type adduct. Sur-
prisingly, to obtain the product of 3 and 5a in reasonable
r
10.1021/ol401425s
Published on Web 06/11/2013
2013 American Chemical Society

Table 1. Preparation of Zinc Enolate Equivalent from Phenyl
Isocyanate and Bis(iodozincio)methanea
Scheme 2. Addition Reaction of 3 with Benzaldehyde
entry
solvent
THF
t/°C
yield of 4/%
1
2
3
4
5
20
50
80
80
80
48
73
99
99
0b
In Scheme 3, optically active aminoalcohols 7, which
were derived from L-proline and effective for the cataly-
tic asymmetric addition of alkylzinc to aldehydes, were
added in a catalytic amount (30 mol %) to activate the
enolate equivalent 3 for the addition to p-tolyl aldehyde
(5b). In all cases, asymmetric induction was observed.
Among 7, (S)-bis(4-fluorophenyl)(1-methylpyrrolidin-
2-yl)methanol (7g)11 induced the highest enantioselec-
tivity (87% ee).
toluene
hexane
a 1 (0.5 M in THF, 1.0 mL) and 2 (0.5 mmol) in the solvent (1.0 mL)
were used. b The isocyanate was recovered.
yield, a temperature of over 100 °C was necessary. Con-
sidering the low reactivity of the enolate equivalent 3
with the aldehyde, it may not have an O-enolate form 3c
but an alkylzinc form 3a,b.5 It is well-known that the low
reactivity of alkylzinc can be improved by the addition of
an aminoalcohol. This activation is crucial for asymmetric
induction. Several enantioselective alkylations of alde-
hydes by organozinc reagents have been performed in the
presence of an optically active aminoalcohol.6 Along this
line, the reaction of 3 with aldehydes in the presence of
an optically active aminoalcohol was examined to perform
an asymmetric induction in the aldol-type reaction.
Although a variety of catalytic asymmetric alkylations
using an organozinc reagent has been developed, examples
of a catalytic asymmetric aldol-type reaction using zinc
enolate are limited.7 A tandem-type reaction, which con-
tains the asymmetric 1,4-addition of organozinc to enone
in the presence of a chiral catalyst followed by the 1,2-
addition of the formed enone to aldehyde, showed high
asymmetric induction in the first 1,4-addition, but the
second aldol-type reaction did not always show reasonable
diastereoselectivities.8 Several examples of a Reformatsky
reaction using a stoichiometric amount of a chiral source9
and only a few examples of catalytic asymmetric zinc-
enolate aldol reactions10 had already been reported.
Scheme 3. Asymmetric Induction in the Reaction of 3 with
p-Tolaldehyde in the Presence of L-Proline Derived
Aminoalcohols
Table 2. Optimization of the Reaction of 3 with p-Tolaldehyde
(5b) in the Presence of a Catalytic Amount of 7ga
1
(5) (a) H NMR analysis for 3 implied the alkyl zinc structure (SI).
(b) Hlavinka, M. L.; Hagadorn, J. R. Organometallics 2005, 24, 4116.
(6) (a) Soai, K.; Ookawa, A.; Ogawa, K.; Kaba, T. J. Chem. Soc.,
Chem. Commun. 1987, 467. (b) Oguni, N.; Omi, T. Tetrahedron Lett.
1984, 25, 2823. (c) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am.
Chem. Soc. 1986, 108, 6071. (d) Smaardijk, A.; Wynberg, H. J. Org.
Chem. 1987, 52, 135. (e) Yang, X.; Shen, J.; Da, C.; Wang, R.; Choi,
M. C. K.; Yang, L.; Wong, K. Tetrahderon: Asymmetry 1999, 10, 133.
(7) Lombardo, M.; Trombini, C. The Chemistry of Zinc Enolate. In
The Chemistry of Organozinc Compounds Part 2; Rappoport, Z., Marek, I.,
Eds.; John Wiley & Sons: West Sussex, England; 2006; pp 797À861.
(8) (a) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries,
A. H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620. (b) Alexakis, A.;
Trevitt, G. P.; Bernardinelli J. Am. Chem. Soc. 2001, 123, 4358.
x/
y/
time/
h
yield
ee/
%
entry
equiv
mol %
of 6b
1
2
3
4
5
2.0
2.0
2.5
2.5
2.5
30
30
30
20
10
48
72
72
72
72
35
52
99
68
56
79
77
84
84
84
(9) (a) Soai, K.; Oshio, A.; Saito, T. J. Chem. Soc., Chem. Commun.
ꢀ
ꢀ
1993, 811. (b) Andres, J. M.; Pedrosa, R.; Perez-Encabo, A. Tetrahedron
2000, 56, 1217. (c) Fujiwara, Y.; Katagiri, T.; Uneyama, K. Tetrahedron
Lett. 2003, 44, 6161.
a 5b (0.5 mmol) was used. In the reaction of entry 1, 1 (0.5 M in THF,
2.0 mL) and 2 (1.0 mmol) in toluene (2.0 mL) were premixed for 0.5 h at
80 °C; 7g (0.15 mmol) in toluene (0.5 mL) and 5b (0.5 mmol) in toluene
(1.0 mL) were added at À40 °C subsequently.
(10) (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003.
ꢀ
ꢀ~
ꢀ
(b) Fernadez-Ibanez, M. A.; Marcia, B.; Minnaard, A. J.; Feringa, B. L.
Angew. Chem., Int. Ed. 2008, 47, 1317. (c) Cozzi, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 2951.
Org. Lett., Vol. 15, No. 13, 2013
3379

Table 3. Examples of the Reaction of 3 with Aldehydes (5) in the
Presence of a Catalytic Amount of 7ga
Scheme 4. Asymmetric Induction in Chemoselective
Reformatsky-Type Reaction
entry
R in 6
yield/%
ee/%b
1
4-MeC6H4À
2-MeC6H4À
4-FC6H4À
4-ClC6H4À
4-BrC6H4À
4-MeOC6H4À
4-t-BuC6H4À
mesityl
6b
6c
6d
6e
6f
99
91
77
76
47
65
57
63
89
73
92
45
49
84
84
89
79
77
94
84
84
88
94
76
76
83
2
The moderate reactivity of the enolate equivalent can
realize asymmetric induction in the aldol reaction in the
presence of a ketone group. As shown in Scheme 4, the
treatment of ketoaldehyde 8 with 3 afforded the corre-
sponding product 9 in 81% yield with 93% ee.
3
4
5
6
6g
6h
6i
7
8
Because the enolate equivalent 3 prepared by the addi-
tion of bis(iodozincio)methane (1) to phenyl isocyanate
possesses only low nucleophilicity, the activation by addi-
tion of an aminoalcohol catalyst makes it a highly selective
synthetic reagent as an amide enolate equivalent. Prepara-
tion of a metal enolate of amide has been performed
by treatment of an amide with a strong base or a reduction
of R-haloamide with a low valent metal. When these
procedures are applied to asymmetric induction methods,
the existing conjugate acid or Lewis acidic metal halide,
which was formed stoichiometrically in the reaction mix-
ture during the preparation, would cause poor asymmetric
induction. The present method, a direct introduction of
the CÀZn bond using a gem-dizinc reagent, however, does
not suffer from these obstacles. Preparations of various
enolate equivalents from a gem-dizinc reagent and hetero-
cumelene are studied now in our group.
9
2-naphtyl
2-thienyl
2-furyl
6j
10
11
12
13
6k
6l
MeÀ
6m
6n
t-BuÀ
a 1 (0.5 M in THF, 2.5 mL) and 2 (1.25 mmol) in toluene (2.0 mL)
were premixed for 0.5 h at 80 °C; 7g (0.15 mmol) in toluene (0.5 mL) and
5 (0.5 mmol) in toluene (1.0 mL) were added at À40 °C subsequently.
b The absolute configuration of the product in entry 11 was determined
by the authentic sample (see ref 12). Absolute configurations in other
products were estimated by referring to this result.
The optimization of the addition of enolate equivalent 3
to p-tolyl aldehyde in the presence of 7g was examined
as shown in Table 2. When the reaction was performed
by adding 2 equiv of 3 to 5b in the presence of 30 mol % 7g,
the adduct 6b was obtained in 99% yield with 84% ee.
As shown in Table 3, various aldehydes were examined
under the conditions of entry 3 in Table 2. In all cases, the
products were obtained with over 76% ee.12 Compared to the
already reported catalytic asymmetric Reformatsky-type re-
action, the present results show competitive optical yields.10b,c
Acknowledgment. This work was supported financially
by the Japanese Ministry of Education, Culture, Sports,
Science and Technology.
(11) (a) Zhao, G.; Li, X.-G.; Wang, X.-R. Tetrahedron; Asymmetry
2001, 12, 399. (b) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am.
Chem. Soc. 1987, 109, 7111.
Supporting Information Available. Experimental pro-
cedures including spectroscopic and analytical data.
This material is available free of charge via the Internet
at http://pubs.acs.org.
(12) The value of ee was detemined by HPLC analysis using a chiral
column. The absolute configuration of 6l was determined by the optical
20
rotation ([R]D À21.2 (c 0.70, CH2Cl2)) by comparison with the
reported value. Demizu, Y.; Kubo, Y.; Matsumura, Y.; Onomura, O.
Synlett 2008, 433.
The authors declare no competing financial interest.
3380
Org. Lett., Vol. 15, No. 13, 2013