Indium-mediated one-pot three-component reaction of aromatic amines, enol ethers, and allylic bromides

Article abstract of DOI:10.1021/ol052326o

A new and efficient indium-mediated one-pot three-component reaction for the synthesis of N-aryl-substituted homoallylamines from aromatic amines, enol ethers, and allylic bromides in THF at room temperature is described.

Full text of DOI:10.1021/ol052326o

ORGANIC
LETTERS
2
006
Vol. 8, No. 2
95-198
Indium-Mediated One-Pot
Three-Component Reaction of Aromatic
Amines, Enol Ethers, and Allylic
Bromides
1
Taeg-Su Jang,†,‡ Il Whea Ku, Min Seok Jang, Gyochang Keum,
†,‡
†
†
†
‡
,†
Soon Bang Kang, Bong Young Chung, and Youseung Kim*
Biochemicals Research Center, Korea Institute of Science and Technology,
Cheongryang P.O. Box 131, Seoul 130-650, Korea, and Department of Chemistry,
Korea UniVersity, Seoul 136-701, Korea
yosekim@kist.re.kr
Received September 26, 2005
ABSTRACT
A new and efficient indium-mediated one-pot three-component reaction for the synthesis of N-aryl-substituted homoallylamines from aromatic
amines, enol ethers, and allylic bromides in THF at room temperature is described.
6
Homoallylic amines are important fundamental building
blocks for the synthesis of many nitrogen-containing natural
products and many biologically active compounds. More-
property. Recently, indium reagents have evolved as mild
Lewis acids, increasing the rate of the reaction and affording
high regio-, chemo-, and stereoselectivity in various chemical
1
2
7
over, N-aryl homoallylic amine compounds show potent
transformations.
Our continuous efforts in the area of indium led us to
determine the utility of allylic indium compounds for the
reaction of arylamines and enol ethers resulting in the
construction of homoallylic amines (Scheme 1). This study
3
8
antifungal activity. A variety of synthetic methods have been
4
developed for the preparation of homoallylamines. In
particular, the Lewis acid catalyzed allylation of aldimines
provides a useful procedure for their synthesis, and diverse
homoallylamines are rapidly accessible by a direct three-
component reaction, which requires an aldehyde, an amine
(
or an amide), and a presynthesized allylic organometallic
Scheme 1. Indium-Mediated Reaction of Aromatic Amines,
5
(Si, Sn, or Ge) reagent. The chemistry of metallic indium
Enol Ethers, and Allylic Bromides
is of current interest in organic synthesis due to its mediation
ability for many organic transformations and its unique
†
Korea Institute of Science and Technology
Korea University
‡
(1) (a) Ovaa, H.; Stragies, R.; van der Marel, G. A.; van Boom, J. H.;
Blechert, S. Chem. Commun. 2000, 1501-1502. (b) Hunt, J. C. A.; Laurent,
P.; Moody, C. J. Chem. Commun. 2000, 1771-1772.
(
2) (a) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895-
1
946. (b) Bloch, R. Chem. ReV. 1998, 98, 1407-1438.
(3) Vargas M., L. Y.; Castelli, M. V.; Kouznetsov, V. V.; Urbina G., J.
M.; Lopez, S. N.; Sortino, M.; Enriz, R. D.; Ribas, J. C.; Zacchino, S.
demonstrated that enol ethers could be used as an aldehyde
equivalent for the generation of imines in the one-pot
reaction.
Bioorg. Med. Chem. 2003, 11, 1531-1550.
(
14.
4) Puentes, C. O.; Kouznetsov, V. J. Heterocycl. Chem. 2002, 39, 595-
6
1
0.1021/ol052326o CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/16/2005

We wish to disclose herein an efficient indium-mediated
one-pot three-component reaction for the synthesis of N-aryl-
substituted homoallylamines from aromatic amines, enol
ethers, and allylic bromides. Thus treatment of allylic indium
compounds, generated in situ from allyl bromides and indium
powder, with aromatic amines and enol ethers in THF at
room temperature under argon for 2-24 h resulted in the
formation of the corresponding homoallylic amine derivatives
in moderate to good yields.
Table 2. Indium-Mediated Reaction of Allyl Bromide, Ethyl
Vinyl Ether, and Various Amines
In our initial study, the reaction of various vinylic ether
type compounds with aniline and allyl bromide was inves-
tigated to optimize the reaction conditions (Table 1).
Table 1. Indium-Mediated Reaction of Allyl Bromide, Aniline,
and Various Vinylic Ether Compounds
entry
R4
isolated yield(%)
1
2
3
4
Et
Bu
Ac
SiMe3
91
84
21
59
Among them, ethyl vinyl ether was the best choice in this
case, resulting in the formation of the corresponding ho-
moallylic amine in 91% yield (entry 1). Employing vinyl
detected in the crude reaction mixtures, whereas the reaction
of aliphatic amines gave allylic amines exclusively via direct
allylation reaction of amines.
9
acetate led to poor result because acetanilide was formed
The result of indium-mediated reactions of various aro-
matic amines with ethyl vinyl ether and allyl bromide is
shown in Table 2. The reaction of anilines substituted with
halogen, alkyl, or electron-donating alkoxy groups proceeded
(entry 3), and this reaction was applicable to trimethylsilyl
enol ether (entry 4). No trace of aromatic allylamines was
(
5) (a) Giammaruco, M.; Taddei, M.; Ulivi, P. Tetrahedron Lett. 1993,
4, 3635-3638. (b) Kobayashi, S.; Busujima, T.; Nagayama, S. Chem.
Commun. 1998, 19-20. (c) Akiyama, T.; Iwai, J. Synlett 1998, 273-274.
d) Aspinall, H. C.; Bissett, J. S.; Greeves, N.; Levin, D. Tetrahedron Lett.
002, 43, 323-326. (e) Choudary, B. M.; Chidara, S. Sekhar, Ch. V. R.
Synlett 2002, 1694-1696.
3
(
2
Table 3. Indium-Mediated Reaction of Allyl Bromide,
Aromatic Amines, and Various Enol Ether Type Compounds
(
6) (a) Li, C. J.; Chan, T. H. Tetrahedron 1999, 55, 11149-11176. (b)
Podlech, J.; Maier, T. C. Synthesis 2003, 633-655. For recent examples of
indium-mediated allylation of imines and CdN systems, see: (c) Vilaivan,
T.; Winotapan, C.; Banphavichit, V.; Shinada, T.; Ohfune, Y. J. Org. Chem.
2
005, 70, 3464-3471. (d) Cook, G. R.; Maity, B. C., Kargbo, R. Org.
Lett. 2004, 6, 1741-1743 and references therein.
7) (a) Babu, G.; Perumal, P. T. Aldrichimica Acta 2000, 33, 16-18.
b) Ranu, B. C. Eur. J. Org. Chem. 2000, 2347-2356.
8) (a) Kang, S.; Jang, T.-S.; Keum, G.; Kang, S. B.; Han, S.-Y.; Kim,
(
(
(
Y. Org. Lett. 2000, 2, 3615-3617. (b) Park, L.; Keum, G.; Kang, S. B.;
Kim, K. S.; Kim, Y. J. Chem. Soc., Perkin Trans. 1 2000, 4462-4463. (c)
Cho, S.; Keum, G.; Kang, S. B.; Han, S.-Y.; Kim, Y. J. Org. Chem. 2003,
6
8, 180-182. (d) Jang, T.-S.; Keum, G.; Kang, S. B.; Chung, B. Y.; Kim,
Y. Synthesis 2003, 775-779.
9) Typical Procedure. A mixture of indium (2 mmol) and allyl bromide
3 mmol) in THF (2 mL) was stirred for 1 h at room temperature under
(
(
argon. Aniline (1 mmol) and ethyl vinyl ether (2 mmol) were added to the
reaction mixture. After stirring for 2 h, the reaction was quenched with
saturated aqueous ammonium chloride (5 mL). The whole mixture was
extracted with ethyl acetate (3 × 20 mL). The combined organic layers
were washed with water (20 mL), dried over MgSO4, and evaporated. A
pure product was obtained by flash column chromatography on silica gel
1
(
n-hexane/ethyl acetate ) 20:1): H NMR (300 MHz, CDCl3) δ 7.22 (t,
2
5
2
H, J ) 7.8 Hz), 6.73 (t, 1H, J ) 7.4 Hz), 6.64 (d, 2H, J ) 7.8 Hz),
.95-5.81 (m, 1H), 5.18-5.13 (m, 2H), 3.60 (sxt, 1H, J ) 6.3 Hz), 2.44-
1
3
a
.36 (m, 1H), 2.31-2.22 (m, 1H), 1.24 (d, 3H, J ) 6.6 Hz); C NMR (75
1-Ethoxycyclohex-1-ene was prepared from cyclohexanone and tri-
1
0
MHz, CDCl3) δ 147.3, 134.9, 129.2, 117.5, 117.0, 113.2, 47.9, 40.8, 20.3;
ethylorthoformate using p-toluenesulfonic acid by the known procedure.
Reaction was carried out at 60 °C (bath temperature) for 24 h.
+
b
MS (EI, 70 eV) m/z (%) 161 (M , 7.8), 120 (100), 104 (4.3), 91 (3.4), 77
(12.0).
196
Org. Lett., Vol. 8, No. 2, 2006

to give the corresponding homoallylamines in high yields.
In the case of 4-aminobenzonitrile, an electron-deficient
aromatic amine, only a small amount of the product was
obtained (entry 6).
Table 4. Indium-Mediated Reaction of p-Anisidine, Ethyl
Vinyl Ether, and Substituted Allylic Bromides
Next, the generality of the indium-mediated reaction was
examined with various enol ether type reagents, and the
results are listed in Table 3. In all cases, the three-component
one-pot reaction of enol ether type compounds with aromatic
amines and allyl bromide proceeded smoothly to give the
corresponding homoallylic amine. Under these conditions
2,3-dihydrofuran, a cyclic enol ether, undergoes ring opening
to generate the homoallylic amine derivative bearing a
hydroxypropyl side chain in a good yield (entry 1).
The reactions of â-substituted-(E)-vinyl ethers gave the
corresponding product in lower yields. When 1-propenyl
ether was treated with aniline or p-anisidine in the presence
of allyl bromide and indium powder, the expected homoal-
lylic amines were isolated in only less than 20% yields
a
Diastereomeric ratio was determined by GC.
(entries 2 and 6). In the case of methyl trans-3-methoxy-
acrylate no reaction occurred at room temperature; however,
the corresponding homoallylic amine was obtained in 52%
yield at 60 °C for 24 h (entry 5). The low reactivity of methyl
trans-3-methoxyacrylate could be explained by the generation
of the stable enamine adduct through tautomerization of the
imine intermediate formed by elimination of methanol. For
example, under the same reaction conditions, diethyl ethoxy-
methylenemalonate was converted exclusively into the cor-
responding enamine compound at room temperature (Scheme
product was formed via a cascade hydroamination of an ethyl
ether type compound/elimination of an alcohol/allylation of
2).
Scheme 2. Indium-Mediated Reaction of Aniline, Diethyl
Ethoxymethylenemalonate, and Allyl Bromide
Figure 1. Plausible reaction pathway.
an imine intermediate process. First of all, the N,O-acetal
intermediate 4 is formed via R-selective hydroamination of
a vinyl ether 2 with an aromatic amine 1 in the presence of
in situ generated allylic indium reagent 3 from allyl bromide
Further, the three-component reaction of p-anisidine and
13
and indium metal. Then, an imine adduct 5 generated from
via subsequent elimination of an alcohol undergoes
ethyl vinyl ether with various allylic bromides was investi-
gated, and the results are summarized in Table 4. Starting
from γ-substituted allylic bromides such as crotyl bromide,
methyl 4-bromocrotonate, and cinnamyl bromide, the branched
homoallylic amines were obtained exclusively in moderate
yields as a mixture of diastereomers. Their γ-regioselectivi-
ties were analogous to the selectivity observed for the
4
allylation reaction with the allylic indium compound 3 to
give the corresponding homoallylic amine 6. In this reaction,
the allylic indium compound 3 plays a role in both the
generation of an imine intermediate as a Lewis acid and the
allylation reaction of imine as a nucleophile.
The generation of the imine intermediate by the hydroami-
nation/elimination process has been confirmed by the reaction
1
1
indium-mediated allylation of carbonyl compounds and
imines,12 with γ-substituted allylic bromides.
7
of aniline-d . Thus, the one-pot three-component reaction of
The proposed mechanism for the reaction of an aniline,
an ethyl vinyl ether, and an allyl bromide in the presence of
indium metal is illustrated in Figure 1. We suggest that the
aniline-d , ethyl vinyl ether, and allylindium bromide 3
7
proceeded to provide the corresponding homoallylamine
compound 7 with deuterium on the carbon of the methyl
group in 76% isolated yield (Scheme 3).
(10) Yagoub, A. K.; Iskander, G. M. J. Chem. Soc., Perkin Trans. 1
1
977, 697-699.
(
11) Issac, M. B.; Chan, T. H. Tetrahedron Lett. 1995, 36, 8957-8960.
12) (a) Lu, W.; Chan, T. H. J. Org. Chem. 2000, 65, 8589-8594. (b)
(13) An in situ generation of iminium salt from N,O-acetal: Volkmann,
R. A. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 1, pp 355-396.
(
Lu, W.; Chan, T. H. J. Org. Chem. 2001, 66, 3467-3473.
Org. Lett., Vol. 8, No. 2, 2006
197

amines, enol ethers, and allylic bromides. The reaction
showed complete γ-regioselectivity and reasonable diaste-
reoselectivity when γ-substituted allylic bromides were used.
We were able to extend the scope of the utility of indium in
organic synthesis. Further studies on the application of this
protocol to organic synthesis are currently underway in our
laboratory.
7
Scheme 3. Indium-Mediated Reaction of Aniline-d , Ethyl
Vinyl Ether, and Allylindium Bromide
Acknowledgment. This work was fully supported by the
Korea Institute of Science and Technology.
Supporting Information Available: General methods,
characterization data, and spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have described a new and gentle indium-
promoted one-pot three-component reaction for the prepara-
tion of N-aryl-substituted homoallylic amines from aromatic
OL052326O
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Org. Lett., Vol. 8, No. 2, 2006