Synthetic method for the preparation of 2-aminomethyl-1,3-diene derivatives through indium-mediated 1,3-butadien-2-ylation of imines

Article abstract of DOI:10.1021/ol9005213

An efficient method for the preparation of a variety of 2-aminomethyl-1,3-dienes was developed through the reaction of imines with organoindium reagent generated in situ from indium and 1,3-dibromo-2-butyne. Three-component reactions of aldehydes, amines,

Full text of DOI:10.1021/ol9005213

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2401-2404
Synthetic Method for the Preparation of
2-Aminomethyl-1,3-diene Derivatives
through Indium-Mediated
1,3-Butadien-2-ylation of Imines
Dong Seomoon, Jaemyung A, and Phil Ho Lee*
National Research Laboratory for Catalytic Organic Reaction, Department of
Chemistry, and Institute for Molecular Science and Fusion Technology, Kangwon
National UniVersity, Chuncheon 200-701, Republic of Korea
phlee@kangwon.ac.kr
Received March 13, 2009
ABSTRACT
An efficient method for the preparation of a variety of 2-aminomethyl-1,3-dienes was developed through the reaction of imines with organoindium
reagent generated in situ from indium and 1,3-dibromo-2-butyne. Three-component reactions of aldehydes, amines, and organoindium reagents
gave successful results in a one-pot process.
Carbon-carbon bond formation by nucleophilic addition of
carbon nucleophiles to imines is an important tool for
synthesizing complex biologically active nitrogen-containing
compounds.1 While addition of a variety of carbon nucleo-
philes to carbonyl compounds has been extensively inves-
tigated and well established, considerably less successful
results were obtained in the analogous reactions with imines.
The major problems are the relatively low reactivity of
unactivated imines toward nucleophilic addition and depro-
tonation of imines derived from enolizable carbonyl com-
pounds to form enamines. During the last decades, a variety
of carbon nucleophiles have been used in the addition
reaction of imines.2 However, the preparation of 2-amino-
methyl-1,3-diene derivatives through an addition reaction of
(1) (a) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
(b) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27, 13. (c)
Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002,
58, 2253. (d) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.
2002, 35, 984. (e) Alvaro, G.; Savoia, D. Synlett 2002, 651. (f) Zhou, P.;
Chen, B.; Davis, F. A. Tetrahedron 2004, 60, 8003. (g) Friestad, G. K.
Eur. J. Org. Chem. 2005, 3157.
(3) (a) Hosomi, A.; Masunari, T.; Tominaga, Y.; Hojo, M. Bull. Chem.
Soc. Jpn. 1991, 64, 1051. (b) Sheares, V. V.; Wu, L.; Li, Y.; Emmick,
T. K. J. Polym. Sci., Part A: Polym. Chem. 2000, 38, 4070.
(4) Jones, G. D.; Meyer, W. C.; Tefertiller, N. B.; MacWilliams, D. C.
J. Polym. Sci. 1970, 8, 2123.
(2) (a) Beuchet, P.; Marrec, N. L.; Mosset, P. Tetrahedron Lett. 1992,
33, 5959. (b) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207. (c)
Basile, T.; Bocoum, A.; Savoia, D.; Umani-Ronichi, A. J. Org. Chem. 1994,
59, 7766. (d) Bloch, R. Chem. ReV. 1998, 98, 1407. (e) Kobayashi, S.;
Ishitani, H. Chem. ReV. 1999, 99, 1069. (f) Lu, W.; Chan, T. H. J. Org.
Chem. 2000, 65, 8589. (g) Lu, W.; Chan, T. H. J. Org. Chem. 2001, 66,
3467. (h) Yanada, R.; Kaieda, A.; Takemoto, Y. J. Org. Chem. 2001, 66,
7516. (i) Lee, J. G.; Choi, K. I.; Pae, A. N.; Koh, H. Y.; Kang, Y.; Cho,
Y. S. J. Chem. Soc., Perkin Trans. 1 2002, 1314. (j) Miyabe, H.; Yamaoka,
Y.; Naito, T.; Takemoto, Y. J. Org. Chem. 2004, 69, 1415. (k) Yamada,
K.-I.; Tomioka, K. Chem. ReV. 2008, 108, 2874.
(5) Coulson, D. R. J. Org. Chem. 1973, 38, 1483.
(6) Castagnolo, D.; Renzulli, M. L.; Galletti, E.; Corelli, F.; Botta, M.
Tetrahedron: Asymmetry 2005, 16, 2893.
(7) (a) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon Press: Oxford, U.K., 1990. (b) Oppolzer, W. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon
Press: Oxford, U.K., 1991; Vol. 5, p 315. (c) Kappe, C. O.; Murphree,
S. S.; Padwa, A. Tetrahedron 1997, 53, 14179. (d) Marsault, E.; Toro´, A.;
Nowak, P.; Deslongchamps, P. Tetrahedron 2001, 57, 4243. (e) Nicolaou,
K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem.,
Int. Ed. 2002, 41, 1668.
10.1021/ol9005213 CCC: $40.75
Published on Web 05/07/2009
 2009 American Chemical Society

the 1,3-butadien-2-yl moiety to imines is still rare in organic
reactions. Of these, the Grignard cross-coupling reaction of
2-bromo-3-aminopropene with vinyl bromides suffers from
poor chemoselectivity.3 2-Halomethyl-1,3-dienes, though
quite effective in reacting with secondary amines to give
2-aminomethyl-1,3-dienes, are not convenient to prepare.3b,4
Although 2-aminomethyl-1,3-dienes have been produced by
the reaction of 2 equiv of allene with various amines in the
presence of Pd catalysts, bis(dienyl)amines as a side product
were contaminated.5 Enyne cross metathesis is a good
syntheic method of 2-N-arylmethyl-1,3-butadienes.6 Because
so much is now known about the Diels-Alder reaction,7
we were convinced that when we found an efficient addition
reaction of the 1,3-butadien-2-yl group to imines, then this
reaction would prove useful to synthetic organic chemists
for the synthesis of a variety of 2-aminomethyl-1,3-diene
derivatives as well as six-membered carbocycles. Herein, we
report indium-mediated addition reactions of 1,3-dien-2-yl
indium generated in situ from 1,4-dibromo-2-butyne and
indium with imines or the mixture of aldehyde and amine
for the synthesis of 2-aminomethyl-1,3-diene derivatives
(Scheme 1).
Table 1. Optimization of 1,3-Butadien-2-ylation to Imine 1d
with Indium and 2
ln
2
time yield
(%)b
entry solvent
additivea
(equiv) (equiv) (h)
1
THF
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.0
1.3
2.0
2.7
2.0
2.0
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.0
1.5
2.0
1.5
1.5
1.5
20
20
20
3
0
2
DMF
0
3
Dioxane
H2O
0
4
17(42)
15(38)
32(30)
37(25)
47(19)
70(21)
54(21)
42(19)
86(5)
73(18)
50(38)
55(15)
75(14)
5
H2O-THFc
MeOH
MeOH
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
3
6
3
7
MS-4 Å
2
8
MgSO4
2
9
MgSO4
2
10
11
12
13
14
15
16
MgSO4
5
MgSO4
5
MgSO4
2
MgSO4
2
d
MgSO4-InCl3
2
MgSO4-AcOHe
1
Na2SO4
1
a 1 equiv of MgSO4 or Na2SO4 was used. b Numbers in parentheses
indicate yield of 4d. c H2O:THF ) 3:1. d 20 mol % of InCl3 was used. e 6
equiv of AcOH was used.
Scheme 1. Selective 1,3-Butadien-2-ylation to Imines
12). The use of indium in less than 2 equiv and 2 in less
than 1.5 equiv resulted in a sluggish reaction and gave
lower yields even at longer reaction times (entries 10 and
11). The use of MgSO4-InCl3 and MgSO4-AcOH as an
additive gave the desired product 3d in 50% and 55%
yields together with 4d in 38% and 15% yields, respec-
tively (entries 14 and 15). There are no 6, 7, and 5d
We initially examined the addition reactions of an
organoindium reagent8 generated in situ from indium and
1,4-dibromo-2-butyne (2)9 with imine (1d). The results
are summarized in Table 1. The reaction of 1d with 3
equiv of indium and 1.5 equiv of 2 in THF, DMF, and
dioxane did not proceed (entries 1-3). The use of H2O
gave the desired product 3d in 17% yield through 1,3-
butadien-3-ylation to 1d. Compound 4d was additionally
obtained in 42% yield from benzaldehyde derived from
hydrolysis of imine (entry 4).10 Although the model
reaction produced 3d in 32% yield in MeOH, formation
of 4d (30%) was unavoidable (entry 6). Therefore, we
added drying agents such as 4 Å molecular sieves and
MgSO4 to suppress the hydrolysis of imine 1d (entries 7
and 8). In the case of MgSO4, the yield (47%) of 3d was
increased by 15% (entry 6 vs 8), and formation of 4d was
suppressed (entry 8). EtOH was the best solvent among
several reaction media examined (THF, DMF, dioxane,
H2O, H2O-THF, MeOH, and EtOH) (entries 1-9). The
present reaction was carried out with 1 equiv of MgSO4
in EtOH, producing the desired product 3d in 70% yield
together with 4d in 21% yield (entry 9). With this result
in hand, the stoichiometry of indium and 2 was investi-
gated in detail (entries 10-13). Of the addition reactions
examined, the best results were obtained with 2 equiv of
indium and 1.5 equiv of 2 in the presence of 1 equiv of
MgSO4 at 25 °C for 2 h in EtOH under a nitrogen
atmosphere, affording 3d selectively in 86% yield (entry
1
formed in these reactions. The H and 13C NMR spectra
of 3d are consistent with benzylphenylamine possessing
the 1,3-dien-2-yl group. The four sp2 resonances (100
MHz) of the 1,3-dien-2-yl group appeared at 145.4, 136.8,
117.8, and 115.1 ppm, indicating that compound 3d was
selectively produced.
To demonstrate the scope and limitation of the present
method, we applied this reaction system to a variety of imine
compounds, affording 2-aminomethyl-1,3-diene derivatives
(Table 2). Under the optimized conditions, imine 1a gave
the 1,3-diene 3a and allenylmethylamine 5a in 61% and 5%
yields, respectively (entry 1). Treatment of 1b with indium
(8) (a) Alcaide, B.; Almendros, P.; Rodriguez-Acebes, R. J. Org. Chem.
2002, 67, 1925. (b) Alcaide, B.; Almendros, P.; Campo, T. M.; Rodrguez-
Acebes, R. Tetrahedron Lett. 2004, 45, 6429. (c) Alcaide, B.; Almendros,
P.; Rodrguez-Acebes, R. J. Org. Chem. 2005, 70, 3198. (d) Alcaide, B.;
Almendros, P.; Rodrguez-Acebes, R. J. Org. Chem. 2006, 71, 2346. (e)
Lee, K.; Lee, P. H. Chem.sEur. J. 2007, 13, 8877.
(9) Johnson, A. W. J. Chem. Soc. 1946, 1009.
(10) Lu, W.; Ma, J.; Yang, Y.; Chan, T. H. Org. Lett. 2000, 2, 3469.
2402
Org. Lett., Vol. 11, No. 11, 2009

With this result in hand, three component reactions of
aldehydes, amines, and organoindium reagents were inves-
tigated in a one-pot process (Table 3). The three component
Table 2. Selective 1,3-Butadien-2-ylation to Iminesa
Table 3. 1,3-Butadien-2-ylation Using Aldehydes, Amines, and
Organoindium Reagents in One Pota
time
yield
entry imine
R1
R2
(h) product (%)
1
1a
1b
1c
1d
1e
1f
1g
1h
1i
i-Pr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4
7
5
2
2
3
5
2
4
2
1
2
1
4
6
6
6
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
61(5)b
60(4)c
51
2
C6H11
3
PhCHdCH
Ph
4-Cl-C6H4
3-Br-C6H4
2-I-C6H4
4-Me-C6H4
2-Me-C6H4
3-HO-C6H4
4-MeO2C-C6H4 Ph
2-Furyl Ph
4
86(5)c
75(8)b
60(9)c
61(19)c
72(7)b
67(4)b
75(5)b
65(13)b
67(4)c
74(14)c
76(11)c
62(17)c
77(8)c
65(9)c
time
yield
5
Entry
R1
R2
additive
(h) product (%)g
6
7d
8
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
C6H11
Ph
Phb
Phb
Phb
Phb
Ph
Ph
Ph
MgSO4
MgSO4-InCl3
MgSO4
MS-4 Å
AcOH
AcOHe
AcOHf
AcOH
3
3
3
3
2
2
2
6
6
5
5
1
3d
3d
3d
3d
3d
3d
3d
3b
3n
3e
3j
50(18)
60(12)
40(23)
54(18)
64(8)
49(20)
63(9)
48(23)
56(19)
65(10)
59(12)
58(18)
c
9
d
10e
11
12
13
14
15
16e
17e
1j
1k
1l
1m Ph
4-I-C6H4
4-MeO-C6H4
Bn
BnO
4-MeO-C6H4
1n
1o
1p
1q
Ph
Ph
EtO2C
EtO2C
Ph
4-MeO-C6H4 AcOH
Ph
Ph
10 4-Cl-C6H4
11 3-HO-C6H4
12 4-MeO2C-C6H4 Ph
AcOH
AcOH
AcOH
a Reactions were carried out with 1 equiv of 1, 1.5 equiv of 2, and 2
equiv of indium in the presence of 1 equiv of MgSO4 at rt. b 5 Derivatives.
c 4 Derivatives. d Indium:2 ) 3:2.3. e 3 equiv of indium was used.
3k
a Reactions were carried out with 1 equiv of aldehydes, 1.5 equiv of
amines, 1.5 equiv of 2, and 2 equiv of indium in the presence of 1 equiv
of MgSO4 or 1 equiv of AcOH at rt. b 1 equiv of amine was used. c 20 mol
% InCl3 was used. d 3 equiv of MgSO4 wasused. e 0.5 equiv of AcOH was
used. f 2 equiv of AcOH was used. g Numbers in parentheses indicate yields
of 4.
and 2 in the presence of MgSO4 produced the desired product
(3b) in 60% yield (entry 2). In the case of imine-derived
trans-cinnamaldehyde, 1,3-diene 3c was obtained in 51%
yield (entry 3). The presence of either an electron-donating
or electron-withdrawing group, such as chloride, bromide,
iodide, methyl, hydroxyl, and methoxy-carbonyl groups, on
the aromatic ring had little effect on the efficiency and
selectivity of indium-mediated 1,3-butadien-2-ylation of
imine (entries 5-11). Treatment of imine 1e and 1f with
organoindium reagent in the presence of MgSO4 gave the
1,3-dienes (3e and 3f) in 75% and 60% yields, respectively
(entries 5 and 6). Imine 1g reacted with 3 equiv of indium
and 2.3 equiv of 2 to provide 1,3-diene 3g in 61% yield
(entry 7). 1,3-Butadien-2-yl indium smoothly added to imines
1h and 1i to produce 1,3-dienes 3h and 3i in 72 and 67%
yields, respectively (entries 8 and 9). It is noteworthy that
protection of a hydroxyl group on substrates is not necessary
as demonstrated by the reaction of imine 1j (entry 10). Imine
1k bearing a 4-methoxycarbonyl group turned out to be
compatible with the present reaction conditions (entry 11).
2-Furfural worked equally well with the employed reaction
conditions, producing the 1,3-diene 3l in 67% yield (entry
12). Altering the electron demand of the substituents on the
aryl rings of anilines produced the 2-aminomethyl-1,3-dienes
in good yields together with 1,3-butadien-2-yl methanols in
about 10% yields (entries 13-15). Subjecting imines 1m and
1n to the organoindium reagent resulted in 3m and 3n in
74% and 76% yields, respectively (entries 13 and 14).
Reaction of glyoxylic oxime ether 1p and glyoxylic imine
1q with 3 equiv of indium and 1.5 equiv of 2 provided
N-protected R-amino esters 3p and 3q having the 1,3-diene
group in 77% and 65% yields, respectively (entries 16 and
17).
reaction of benzaldehyde, aniline, and organoindium reagent
in situ generated from 2 equiv of indium and 1.5 equiv of
1,4-dibromo-2-butyne (2) in the presence of 1 equiv of
MgSO4 has been carried out at 25 °C for 3 h in EtOH under
a nitrogen atmosphere, affording selectively the desired
product 3d (50%) together with 4d (18%) (entry 1). A variety
of additives, such as MgSO4, MgSO4-InCl3, 4 Å molecular
sieves, and AcOH, were examined to increase the product
yield as well as suppress 4d. Of the additives examined, 1
equiv of AcOH gave the best result (entry 5). Under the
optimum conditions, the desired product 3d was produced
in 64% yield. Treatment of cyclohexanecarbaldehyde and
aniline with indium and 2 afforded 3b in 48% yield in a
one-pot process (entry 8). In situ generated imine 1n was
readily 1,3-butadien-2-ylated with organoindium reagent to
provide 3n in 56% yield (entry 9). We were pleased to obtain
3e and 3j in 65% and 59% yields, respectively, from three
component reactions in a one-pot process (entries 10 and
11). In the case of methyl 4-formylbenzoate, the desired
product 3k was produced in 58% yield together with 4k in
18% yield (entry 12). Although treatment of indium and 2
with a mixture of aldehydes and amines gave an inferior
result in terms of the chemical yields, the present method
efficiently assembled three components in a one-pot process,
producing the 2-aminomethyl-1,3-diene derivatives in good
yield.
In summary, we have developed a convenient protocol for
the synthesis of a variety of 2-aminomethyl 1,3-diene
derivatives through the reactions of imines with organoin-
dium reagents generated in situ from indium and 1,3-
Org. Lett., Vol. 11, No. 11, 2009
2403

dibromo-2-butyne. Three component reactions of aldehydes,
amines, and organoindium reagents gave successful results
in a one-pot process.
Korea Sanhak Foundation. We thank the BK21 program for
the financial support. Dr. Sung Hong Kim at the KBSI
(Daegu) is thanked for obtaining the MS data. The NMR
data were obtained from the central instrumental facility in
Kangwon National University.
Acknowledgment. This work was supported by the Korea
Science and Engineering Foundation (KOSEF) through the
National Research Laboratory Program funded by the
Ministry of Science and Technology (No. M10600000203-
06J0000-20310), by the Korea Research Foundation Grant
funded by the Korean Government (MOEHRD, Basic
Research Promotion Fund (KRF-2006-353-C00030), and by
Supporting Information Available: Experimental pro-
cedure and spectral data (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
OL9005213
2404
Org. Lett., Vol. 11, No. 11, 2009