Umpolung of chiral 2-ethynylaziridines: Indium(I)-mediated stereoselective synthesis of nonracemic 1,3-amino alcohols bearing three chiral centers, catalyzed by palladium(0)

Article abstract of DOI:10.1021/ol006089v

matrix presented R¹ = alkyl, R² = SO₂Ar or Boc, R = alkyl or Ph Treatment of 3-alkyl-2-ethynylaziridines with InI in the presence of Pd(PPh₃)₄ and H₂O gave allenylindium reagents bearing a

Full text of DOI:10.1021/ol006089v

ORGANIC
LETTERS
2
000
Vol. 2, No. 14
161-2163
Umpolung of Chiral 2-Ethynylaziridines:
Indium(I)-Mediated Stereoselective
Synthesis of Nonracemic 1,3-Amino
Alcohols Bearing Three Chiral Centers,
Catalyzed by Palladium(0)
2
Hiroaki Ohno, Hisao Hamaguchi, and Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity,
1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
t-tanaka@phs.osaka-u.ac.jp
Received May 22, 2000
ABSTRACT
3 4 2
Treatment of 3-alkyl-2-ethynylaziridines with InI in the presence of Pd(PPh ) and H O gave allenylindium reagents bearing a protected amino
group in high yields. Stereoselective addition of the allenylindium to aldehydes affords 2-ethynyl-1,3-amino alcohols bearing three chiral
centers in good yields.
The N-activated or N-unactivated aziridines form a peculiar
class of strained azacyclic compounds, with remarkable
carbon-carbon bond-forming reactions, except for aziridinyl
1
0
anion reagents. One might expect that, if the ethynylaziri-
dines 1 could be converted into a nucleophilic species such
as A in Scheme 1, they would become more valuable
1-6
synthetic potential. Currently, aziridines bearing an alk-
enyl7 or ethynyl group on one of the aziridine-ring carbon
atoms have proven to be extremely useful intermediates for
preparation of various types of natural and synthetic com-
pounds. However, they serve only as electrophiles for
,8
9
(
7) (a) Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F. J. Org. Chem. 1990,
5, 4683. (b) Pearson, W. H.; Bergmeier, S. C.; Degan, S.; Lin, K.-C.;
Poon, Y.-F.; Schkeryantz, J. M.; Williams, J. P. J. Org. Chem. 1990, 55,
719. (c) Spears, G. W.; Nakanishi, K.; Ohfune, Y. Synlett 1991, 91. (d)
5
5
(
1) Padwa, A.; Woolhouse, A. D. In ComprehensiVe Heterocyclic
Wipf, P.; Fritch, P. C. J. Org. Chem. 1994, 59, 4875. (e) Davis, F. A.;
Reddy, V. Tetrahedron Lett. 1996, 37, 4349. (f) Cossy, J.; Blanchard, N.;
Meyer, C. Tetrahedron Lett. 1999, 40, 8361.
Chemistry; Lwowski, W., Ed.; Pergamon: Oxford, 1984; Vol. 7, pp 47-
9
1
3.
(
2) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
(8) (a) Ibuka, T.; Nakai, K.; Habashita, H.; Hotta, Y.; Fujii, N.; Mimura,
N.; Miwa, Y.; Taga, T.; Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1994,
33, 652. (b) Ibuka, T.; Mimura, N.; Aoyama, H.; Akaji, M.; Ohno, H.;
Miwa, Y.; Taga, T.; Nakai, K.; Tamamura, H.; Fujii, N.; Yamamoto, Y. J.
Org. Chem. 1997, 62, 999. (c) Ibuka, T.; Mimura, N.; Ohno, H.; Nakai,
K.; Akaji, M.; Habashita, H.; Tamamura, H.; Miwa, Y.; Taga, T.; Fujii,
N.; Yamamoto, Y. J. Org. Chem. 1997, 62, 2982. (d) Ohno, H.; Mimura,
N.; Otaka, A.; Tamamura, H.; Fujii, N.; Ibuka, T.; Shimizu, I.; Satake, A.;
Yamamoto, Y. Tetrahedron 1997, 53, 12933. (e) Toda, A.; Aoyama, H.;
Mimura, N.; Ohno, H.; Fujii, N.; Ibuka, T. J. Org. Chem. 1998, 63, 7053.
(f) Tamamura, H.; Yamashita, M.; Nakajima, Y.; Sakano, K.; Otaka, A.;
Ohno, H.; Ibuka, T.; Fujii, N. J. Chem. Soc., Perkin Trans. 1 1999, 2983.
(9) (a) Ohno, H.; Toda, A.; Miwa, Y.; Taga, T.; Fujii, N.; Ibuka, T.
Tetrahedron Lett. 1999, 40, 349. (b) Ohno, H.; Toda, A.; Fujii, N.; Takemoto
Y.; Tanaka, T.; Ibuka, T. Tetrahedron 2000, 56, 2811.
(3) Osborn, H. M. I.; Sweeney, J. Tetrahedron: Asymmetry 1997, 8,
693.
(
(
(
4) Rayner, C. M. Synlett 1997, 11.
5) Ibuka, T. Chem. Soc. ReV. 1998, 27, 145.
6) For recent syntheses of aziridines, see: (a) Jeong, J. U.; Tao, B.;
Sagasser, I.; Henniges, H.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 120,
844. (b) Ando, T.; Minakata, S.; Ryu, I.; Komatsu, M. Tetrahedron Lett.
998, 39, 309. (c) Ohno, H.; Ishii, K.; Honda, A.; Tamamura, H.; Fujii, N.;
Takemoto, Y.; Ibuka, T. J. Chem. Soc., Perkin Trans. 1 1998, 3703. (d)
McLaren, A.; Sweeney, J. B. Org. Lett. 1999, 1, 1339. (e) Chuang, T.-H.;
Sharpless, K. B. Org. Lett. 1999, 1, 1435. (f) Ohno, H.; Toda, A.; Fujii,
N.; Miwa, Y.; Taga, T.; Yamaoka, Y.; Osawa, E.; Ibuka, T. Tetrahedron
Lett. 1999, 40, 1331. (g) Ohno, H.; Toda, A.; Miwa, Y.; Taga, T.; Fujii,
N.; Ibuka, T. J. Org. Chem. 1999, 64, 2992.
6
1
1
0.1021/ol006089v CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/20/2000

Scheme 1
Scheme 3
intermediates, e.g., for the synthesis of amino alcohols 2
bearing three chiral centers.
Recently, Marshall and co-workers reported pioneering
work on chiral allenylindium reagents.11 Thus, treatment of
propargylic mesylates with InI and aldehydes in the presence
of catalytic palladium(0) affords ethynyl alcohols in good
to excellent stereoselectivities (45:55-95:5), via allenylin-
dium reagents. However, it is a matter of interest to
investigate the utility of ethynylaziridines as a precursor of
an allenylindium reagent, the stability and reactivity of the
allenylindium bearing an amino group, and regio- and
stereoselectivity in both the reagent formation and addition
to aldehydes. In this communication, we describe a highly
stereoselective synthesis of 2-ethynyl-1,3-amino alcohols 2
by umpolung of ethynylaziridines 1 with indium(I) and a
catalytic amount of palladium(0) (Scheme 1).
Attempted formation of allenylindium could not be realized
3 4
even using one of Marshall’s conditions [InI, Pd(PPh ) ,
11
THF-HMPA]. After considerable experimentation using
InI in various solvents such as DMF, MeOH, or THF, we
found that the desired reagent can be formed using InI and
a catalytic amount of Pd(PPh
an inseparable mixture of 4 and 5 after hydrolysis (4:5 )
1:9, 83%). A similar result was obtained using THF-
HMPA (4:1) in the presence of 1 equiv of H O. It was found
that H O is essential for the formation of the allenylindium
)
3 4
2
in THF-H O (1:1), yielding
9
2
2
We initiated our study by forming the allenylindium
reagent from the known 2,3-trans-2-ethynylaziridine 3a
bearing a protected amino group from 2-ethynylaziridine 3a.
Next, the reaction of the indium reagents prepared from
(
Scheme 2).12 The desired indium reagent could not be
12
2
,3-trans-2-ethynylaziridines 3a-e with isobutyraldehyde
was investigated. As shown in Scheme 3 and Table 1, the
aziridines 3a and 3b were treated with InI (1.3 equiv) and
Scheme 2
the aldehyde (1.5 equiv) in the presence of Pd(PPh
3 4
) (5 mol
%
) and H O (1 equiv) in THF-HMPA (4:1), affording the
2
desired amino alcohols 6a and 6b, respectively (entries 1
and 2). In both cases, the syn,syn-adduct was the only isomer
Table 1. Synthesis of 2-Ethynyl-1,3-amino Alcohols from
2
-Ethynylaziridinesa
entry aziridine Pdb
solvent
product
yieldc
1
2
3
4
5
6
7
8
9
0
1
2
3a
3b
3b
3b
3b
3b
3c
3d
3e
7a
7c
7d
7e
A
A
A
A
A
B
A
A
A
A
A
A
A
THF-HMPA
THF-HMPA
THF
6a
6b
6b
6b
6b
6b
6c
6d
6e
8a
8c
8d
8e
42%
62%
53%
46%
48%
61%
57%
68%
43%
59%
62%
70%
45%
THF-H2O (10:1)
THF-H2O (1:1)
THF-HMPA
THF-HMPA
THF-HMPA
THF-HMPA
THF-HMPA
THF-HMPA
THF-HMPA
THF-HMPA
prepared using indium powder under various reaction condi-
tions in the presence or absence of a palladium catalyst.
(10) Aziridinyl anions are known to be effective precursors of highly
1
1
1
substituted aziridines. (a) Satoh, T. Chem. ReV. 1996, 96, 3303. (b) Vedejs,
E.; Kendall, J. J. Am. Chem. Soc. 1997, 119, 6941. (c) Alezra, V.; Bonin,
M.; Micouin, L.; Husson, H.-P. Tetrahedron Lett. 2000, 41, 651. See also,
Almena, J.; Foubelo, F.; Yus, M. J. Org. Chem. 1994, 59, 3210.
13
(
11) (a) Marshall, J. A.; Grant, C. M. J. Org. Chem. 1999, 64, 696. (b)
Marshall, J. A.; Grant, C, M, J. Org. Chem. 1999, 64, 8214.
12) (a) Ohno, H.; Toda, A.; Fujii, N.; Ibuka, T. Tetrahedron: Asymmetry
998, 9, 3929. (b) Ohno, H.; Toda, A.; Takemoto, Y.; Fujii, N.; Ibuka, T.
J. Chem. Soc., Perkin Trans. 1 1999, 2949.
a
All reactions were carried out at room temperature using palladium
catalyst (5 mol %), InI (1.3 equiv), H2O (1 equiv), and isobutyraldehyde
(1.5 equiv). b A: Pd(PPh3)4; B: Pd(dppf)Cl2‚CH2Cl2. c Isolated yields.
(
1
2162
Org. Lett., Vol. 2, No. 14, 2000

isolated. Unfortunately, THF or a mixed solvent of THF-
O was less effective for the addition reaction toward the
aldehyde (entries 3-5). Both Pd(PPh and Pd(dppf)-
Cl ‚CH Cl can be used for the present transformation
compare entries 2 and 6). Similarly, 2,3-trans-aziridines 3c-
the reaction of the aziridine 3e and 7e with benzaldehyde,
respectively, were treated with NaH to give the tetrahydro-
1,3-oxazin-2-ones 13 and 14. The stereochemistries of 13
and 14 were easily determined by NOE analyses.
One plausible mechanism for the present reductive cou-
pling reaction is shown in Figure 1. Although the exact role
H
2
3 4
)
2
2
2
(
3e also gave syn,syn-adducts 6c-6e exclusively (entries
7-9). In contrast, it was found that 2,3-cis-2-ethynylaziri-
dines 7a, 7c, 7d, and 7e gave anti,syn-adducts 8a, 8c, 8d,
and 8e in >99% selectivities under identical reaction
conditions (entries 10-13, Table 2). It should be noted that
the allenylindium from 2,3-trans-2-ethynylaziridines 3a and
3e bearing a bulky isopropyl group showed lower reactivities
toward the aldehyde, giving the corresponding amino alco-
hols 6a and 6e in relatively low yields (entries 1 and 9).
As shown in Scheme 4, the reaction of the 2,3-trans- and
2,3-cis-2-ethynylaziridines 3c and 7c with benzaldehyde gave
Scheme 4
Figure 1.
of H
by H
2
O is unclear, protonation of the aza-anionic species 16
O is assumed to be an important factor for the effective
2
formation of the allenylindium reagent bearing a protected
amino group.
9a and 10a exclusively. When employing acetaldehyde as
an electrophile, although the 2,3-trans-aziridine 3c yielded
only anti,syn-9b in 70% yield, the corresponding 2,3-cis-
aziridine 7c gave an inseparable mixture of the diastereomeric
amino alcohols 10b (88:12) in 75% yield.1
In conclusion, we have demonstrated a novel utility of
2-ethynylaziridines as a precursor of nucleophilic reagents
by umpolung with indium(I). Allenylindium reagents bearing
a protected amino group were effectively formed by treat-
3
Stereochemical assignments for the synthesized diastere-
omeric amino alcohols were readily made by their transfor-
mation into tetrahydro-1,3-oxazin-2-one derivatives as shown
in Scheme 5. The amino alcohols 11 and 12, prepared by
ment of 2-ethynylaziridines with InI, H O, and catalytic
Pd(0). Subsequent reaction of the indium reagents, prepared
from 2,3-trans-2-ethynylaziridines, with aldehydes afford
syn,syn-2-ethynyl-1,3-amino alcohols exclusively, while the
reagents from 2,3-cis-aziridines give anti,syn-isomers in high
selectivities.
2
Scheme 5
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Sports, and Culture, Japan, which is gratefully acknowl-
edged.
Supporting Information Available: Selected experi-
1
mental procedures and H NMR spectra for all new com-
pounds are provided. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL006089V
(13) Comparison of the NMR spectra of 9b and both isomers of 10b
revealed that they are different from 9b. Considering the mechanistic
pathway shown in Figure 1, 10b would be an epimeric mixture at the
oxygenated carbon.
Org. Lett., Vol. 2, No. 14, 2000
2163