Tandem ene-reaction/hydroamination of amino-olefin and -allene compounds catalyzed by Bi(OTf)3

Article abstract of DOI:10.1039/c0cc05258b

Bi(OTf)₃ was proven to act as an effective catalyst for tandem ene-reaction/hydroamination of amino-olefin and amino-allene compounds with some enophiles, giving rise to functionalized N-heterocycles in good yields.

Full text of DOI:10.1039/c0cc05258b

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COMMUNICATION
Tandem ene-reaction/hydroamination of amino-olefin and -allene
compounds catalyzed by Bi(OTf)3w
Kimihiro Komeyama,* Yuusuke Kouya, Yuuki Ohama and Ken Takaki*
Received 29th November 2010, Accepted 7th March 2011
DOI: 10.1039/c0cc05258b
Bi(OTf)3 was proven to act as an effective catalyst for tandem
ene-reaction/hydroamination of amino-olefin and amino-allene
compounds with some enophiles, giving rise to functionalized
N-heterocycles in good yields.
To test the feasibility of such hypothesis, amino-olefin 1a
was chosen as the model substrate to react with 2 equivalents
of the alcoholic enophile 2a.7 To our delight, the desired
tandem reaction was smoothly proceeded by the Bi(OTf)3
catalyst to afford the desired 2-(2,2-diphenylethyl)pyrrolidine
3a in 11% yield along with the formation of the normal
hydroamination product 4a and the condensation product
5a from the alcohol8 (entry 1, Table 1). On screening solvents
such as DCE, MeCN, 1,4-dioxane, and THF, the condensation
mainly occurred, in which the conversion of 1a was very low
except for in DCE (entries 1–4). In contrast, MeNO2 solvent
drastically improved the yield of 3a up to 64% (entry 5).
Cu(OTf)2 also worked well if the reaction was carried out for a
longer period (entry 6). Fe(OTf)2,3, BiCl3, and Sc(OTf)3
provided moderate yields (entries 7–10), while Zn(OTf)2 and
TfOH were sluggish (entries 11 and 12). In contrast, no desired
product was obtained using PtCl2 and PdCl2 catalysts, instead,
4a was predominantly yielded (entries 13 and 14).
A tandem reaction involving multi-step transformations reduces
synthetic steps and incidental wastes to greatly improve synthetic
efficiency.1 There has been a growing interest in the development
of multi-functional catalytic processes, wherein a single catalyst
promotes some transformations without additional reagents and
purifications during the sequential reactions.2
N-Heterocycles are ubiquitous subunits for biologically
active substances.3 Although a diverse set of their synthetic
methods have been reported, there is a continuous need for
new protocols which can produce functionalized N-heterocyclic
substructures in an atom-economical manner.
Recently, we have demonstrated the s,p-dual chelation
effect4,5d of borderline metal complexes, particularly Bi and
Fe catalysts, to hard (heteroatoms) and soft (olefins and
alkynes) bases. These catalysts make the two reaction sites
so close as to effectively promote heterofunctionalizations of
olefins and alkynes.5 With these considerations in mind, we
envisaged that these catalysts might induce two different types
of reactions such as ene-reaction and hydroamination by
means of the s,p-dual chelation effect (Scheme 1). Herein,
we would like to describe a novel tandem ene-reaction/
hydroamination of amino-olefin and -allene compounds with
various enophiles using a Bi(OTf)3 catalyst.6
Table 1 Screening of conditions
Product and yielda (%) Conv.a
(%)
3a
4a
5a
Entry Catalyst Solvent
Time/h
1a
1
2
3
4
5
6
7
8
Bi(OTf)3 DCE
Bi(OTf)3 MeCN
Bi(OTf)3 1,4-Dioxane 23
17
17
11
6
0
7
4
8
2
21
9
11
23
3
9
8
25
9
12
11
8
82
29
39
5
Bi(OTf)3 THF
40
2
0
64 (60)
Bi(OTf)3 MeNO2
Cu(OTf)2 MeNO2
Fe(OTf)3 MeNO2
Fe(OTf)2 MeNO2
100
88
94
81
69
30
28
20
100
96
24
17
48
24
9
23
20
6
60
38
28
30
10
8
6
0
0
24
9
Scheme 1 Tandem ene-reaction/hydroamination.
15
12
60
16
70
3
9
10
11
BiCl3
MeNO2
Sc(OTf)3 MeNO2
Zn(OTf)2 MeNO2
Department of Chemistry and Chemical Engineering, Graduate School
of Engineering, Hiroshima University, 1-4-1 Kagamiyama,
Higashi-Hiroshima, Japan. E-mail: kkome@hiroshima-u.ac.jp;
Fax: +81 82 424 5494; Tel: +81 82 424 7737
12b TfOH
MeNO2
MeNO2
MeNO2
5
86
80
13
14
PtCl2
PdCl2
8
1
w Electronic supplementary information (ESI) available: Experimental
details and characterization data. CCDC 803452. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc05258b
a
Determined by 1H NMR. Value in parenthesis indicates the isolated
b
yield. 20 mol% TfOH was used.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5031–5033 5031

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Table 2 Reaction of amino-olefin (1a) with alcoholic enophiles 2
rings attached to halogen functions, Cl and F, at the para-
position did not participate in the reaction, wherein such benzyl
alcohols were recovered unchanged. It would indicate that
appropriate weakness of the benzylic C–O bond is necessary to
carry out the present tandem reaction. Unsymmetrical alkylaryl
methanols 2g–i were permitted to react with 1a, giving rise to
the corresponding products 3g–i with two diastereoisomers
(entries 6–8). Propargyl alcohols also worked well, leading to the
homo-propargyl pyrrolidines 3j and 3k (entries 9 and 10).
Entry
2
Time/h
Product
Yielda (%)
1
2
R = OMe: 2b
R = Cl: 2c
6
5
3b
3c
51
45
ð1Þ
This protocol could be applied to other types of amino-olefins
like one carbon-elongated amino-olefin 1b and trisubstituted
olefin 1c (Scheme 2). Interestingly, these reactions produced
piperidine skeletons 6a and 6e (from 1b), and 7a and 7e (from 1c)
in which the enophiles attached to the less hindered vinyl
position of the starting olefins.9 Additionally, we found that
the present reaction was capable of using vinyl ketone as an
enophile. Thus, the tandem reaction of 1a with methyl vinyl
ketone (8a) produced the pyrrolidyl ketone 9a (eqn (1)), whose
skeleton is reported to constitute an important building block
for indolizidine compounds.10
3
5
3d
44
4
5
3
7
3e
3f
51
45
Based on these results, we postulated a mechanism for the
present tandem ene-reaction/hydroamination as shown in
Scheme 3. Considering the different reactivities of the bismuth
and Brønsted acid (entries 5 and 12 in Table 1), the bismuth
complex could coordinate to the enophile and the olefin moiety
of 1, efficiently leading to generation of the carbocation inter-
mediate A, in contrast, the Brønsted acid would activate only
enophiles. Sequential trapping of the cation A with the intra-
molecular N-nucleophile might give the desired products 3, 6,
and 9a (path a).11 However, formation of olefin A0 from A (path b)
to sequent Bi-catalyzed hydroamination would not be ruled out.
Because, we confirmed that Bi(OTf)3-catalyzed ene-reactions
of a-methylstyrene with benzyl alcohol 2f or vinyl ketone 8a
smoothly proceeded to provide highly substituted styrenes under
same conditions (Scheme 4).12 In addition, hydroamination of
77
[64 : 36]
6
6
3g
64
7
8
R = Me: 2h
6
3
3h
3i
[64 : 36]
86
[62 : 38]
R = cyclopropyl: 2i
44
[54 : 46]
9
5
3
3j
10
3k
56
a
Isolated yield.
With the optimized conditions, we next studied the scope of
alcoholic enophiles (Table 2). Diaryl methanols 2b–d with
different substituents efficiently provided the tandem reaction
products 3b–d in good yields (entries 1–3). Although in the case
of monoaryl methanols 3e and 3f possessing electron-rich phenyl
rings were well tolerated (entries 4–6), electron-deficient phenyl
Scheme 2
c
5032 Chem. Commun., 2011, 47, 5031–5033
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of the bismuth would be attributable to the unique activation
mode: s,p-dual chelation. In the initial step of the present
reaction, it would proceed via the carbocation intermediate,
thus it could be an ene reaction-like process. Further
investigation for the mechanistic detail and broadening the
synthetic application of this tandem reaction is currently
underway in our laboratory.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology of Japan. Finally, we thank Dr
H. Fukuoka for single crystal X-ray analysis of 11a.
Scheme 3 A plausible reaction mechanism.
Notes and references
1 For recent reviews, see: (a) A. Ajamian and J. L. Gleason, Angew.
Chem., Int. Ed., 2004, 43, 3754; (b) J.-C. Wasilke, S. J. Obrey,
R. T. Baker and G. C. Bazan, Chem. Rev., 2005, 105, 1001;
(c) B. M. Trost, N. Maulide and R. C. Livingston, J. Am. Chem.
Soc., 2008, 130, 16502; (d) N. Shindoh, Y. Takemoto and K. Takasu,
Chem.–Eur. J., 2009, 15, 12168; (e) K. C. Nicolaou and J. S. Chen,
Chem. Soc. Rev., 2009, 38, 2993; (f) J. Poulin, C. M. Grise-Bard and
L. Barriault, Chem. Soc. Rev., 2009, 38, 3092.
Scheme 4
2 (a) G. Liu and X. Lu, Org. Lett., 2001, 3, 3879; (b) R. Lira and
J. P. Wolf, J. Am. Chem. Soc., 2004, 126, 13906.
3 D. O’Hagan, Nat. Prod. Rep., 2000, 17, 435.
similar amino-olefins 1a and 1b to A0 occurred by the Bi(OTf)3
catalyst in quantitative yield. In the case of 1c, tertiary carbo-
cations could appear at the highly substituted sp2-carbon of
olefin, and then followed by trapping with an amino group or by
cyclizations of generated amino-olefins to yield 7a and 7e.
Finally, we have applied this tandem reaction to amino-allene
10 with various vinyl ketones 8 (Table 3).13 The tandem reaction
products 11a–e were obtained in good yields (entries 1–5),
wherein the moiety of vinyl ketone was connected to the center
carbon of the starting allene function.14 Compared with the
amino-olefins, the tandem reaction of the amino-allene would
produce 11 via allyl cation B or diene B0 intermediates. Such
species are known to be good acceptors for N-nucleophiles.15
In summary, we have developed a new bismuth-catalyzed
tandem ene-reaction/hydroamination of amino-olefin and -allene
compounds with benzyl alcohols or vinyl ketones, leading to
the highly functionalized N-heterocycles in good yields under
mild conditions. In this reaction, the excellent catalytic activity
4 (a) N. Asao, T. Oishi, K. Sato and Y. Yamamoto, J. Am. Chem.
Soc., 2001, 123, 6931; (b) Y. Yamamoto, J. Org. Chem., 2007, 72,
7817; (c) N. Asao, T. Kasahara and Y. Yamamoto, Tetrahedron
Lett., 2001, 42, 7903.
5 (a) K. Komeyama, T. Morimoto and K. Takaki, Angew. Chem., Int.
Ed., 2006, 45, 2938; (b) K. Komeyama, Y. Mieno, S. Yukawa,
T. Morimoto and K. Takaki, Chem. Lett., 2007, 752;
(c) K. Komeyama, T. Morimoto, Y. Nakayama and K. Takaki,
Tetrahedron Lett., 2007, 48, 3259; (d) K. Komeyama, K. Takahashi
and K. Takaki, Org. Lett., 2008, 10, 5119; (e) K. Komeyama,
M. Miyagi and K. Takaki, Heteroat. Chem., 2008, 19, 644;
(f) K. Komeyama, K. Takahashi and K. Takaki, Chem. Lett.,
2008, 602; (g) K. Komeyama, R. Igawa, T. Morimoto and
K. Takaki, Chem. Lett., 2009, 724; (h) K. Komeyama, M. Miyagi
and K. Takaki, Chem. Lett., 2009, 224; (i) K. Komeyama, N. Saigo,
M. Miyagi and K. Takaki, Angew. Chem., Int. Ed., 2009, 48, 9875.
6 H. G. Iloughmane and C. L. Roux, in Acid Catalysis in Modern
Organic Synthesis, ed. H. Yamamoto and K. Ishihara, Wiley-VCH
Verlag GmbH
551–588.
& Co. KGaA, Weinheim, 2008, vol. 2, pp.
7 Although we have tried the reaction of 1a with traditional carbonyl-
enophiles such as benzaldehyde, hexanal, and phenylglyoxal,
analytical pure products were not isolated because a complex
mixture was produced in these reactions.
Table 3 Reaction of amino-allene 10 with vinyl ketones 8
8 N. Komatsu, J.-Y. Ishida and H. H. Suzuki, Tetrahedron Lett.,
1997, 38, 7219.
9 We investigated reactions of other amino-olefins having a terminal
olefin (RCHQCH2) and a 1,2-disubstituted one (RCHQCHMe)
with 2a. The former did not provide the desired product, in
contrast, the latter yielded a complex mixture.
10 (a) Y. Watanabe, H. Iida and C. Kibayashi, J. Org. Chem., 1989,
54, 4088; (b) P. L. McGrane and T. Livinghouse, J. Org. Chem.,
1992, 57, 1323; (c) D. F. Taber, P. B. Deker and L. J. Silverberg,
J. Org. Chem., 1992, 57, 5990; (d) G. V. Thanh, J.-P. Celerier and
G. Lhommet, Tetrahedron: Asymmetry, 1996, 7, 2211.
11 L. A. Adrio and K. K. Hill, Chem. Commun., 2008, 2325.
12 G. Shibitha, R. E. Venkata and J. S. Yadav, Synthesis, 2002,
409.
13 When this reaction was tested in following solvents, DCE, MeCN,
THF, Et2O, and 1,4-dioxane, aza-Michael addition mainly
proceeded, leading to N-(6-methylhepta-4,5-dien-1-yl)-N-(3-oxobutyl)-
tosylamine in 28, 20, 100, 100, and 93% NMR yields, respectively.
14 The exact structure of 11a was determined by single crystal X-ray
analysis, see ESIw.
Entry
8
Time/h
Products and yielda (%)
1b
2
3
4
Me (8a)
Ph (8b)
4-MeC6H4 (8c)
4-MeOC6H4 (8d)
4-ClC6H4 (8e)
4
6
1
2
1
11a
11b
11c
11d
11e
84
62
62
59
49
5
15 (a) H. Qin, N. Yamagiwa, S. Matsunaga and M. Shibasaki, Angew.
Chem., Int. Ed., 2007, 46, 409; (b) H. Qin, N. Yamagiwa, S. Matsunaga
and M. Shibasaki, J. Am. Chem. Soc., 2006, 128, 1611.
a
b
Isolated yield. 25 1C.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5031–5033 5033