to be effective in activating CꢀC multiple bonds toward
the addition of various functional groups.5 In particular,
the silver-catalyzed 5-endo-trig cyclization of R-aminoal-
lenes hasbeen wellestablished.5,6 Inthistransformation, as
outlined in Scheme 2, the vinyl-silver intermediate is
considered to be generated by the intramolecular addition
of the amine to the activated π-bond. Subsequently, the
resulting C(sp2)ꢀAg bond is rapidly quenched by a proton
to afford the intramolecular hydroamination product.
However, this mechanism suggests that the intermediate
can be trapped by an electrophile other than a proton.7,8
Therefore, if a halogen cation equivalent (Xþ) can inter-
cept the intermediate prior to protonation, a facile and
efficient method for the synthesis of 3-pyrrolines9 bearing a
C(sp2)ꢀX bond can be achieved.
the presence of a catalytic amount of [Ag(phen)OTf]11
indeed provided the desired bromoamination product 2a0.
However, a substantial amount of the hydroamination
byproduct 3a was also formed (Table 1, entries 1 and 2).
Our attempts to improve the reaction by increasing the
amount of the catalyst or NBS were unsuccessful (Table 1,
entries 3 and 4). Hence, to suppress the undesired forma-
tion of 3a, we replaced NBS with N-chlorosuccinimide
(NCS). The use of NCS efficiently suppressed the compe-
titive side reaction, and the chloroamination product 2a12
was obtained in a fairly good yield (Table 1, entry 5).13
Table 1. Optimization of Reaction Conditionsa
Scheme 2. Competition between Protonation and Halogenation
of the Vinyl-Silver Intermediate
yield (%)b
Xþ/base
(mol %)
[Ag]
entry
(mol %)
2
3a
1
NBS/ꢀ
NBS/ꢀ
NBS/ꢀ
NBS/ꢀ
NCS/ꢀ
20 2a0, 14
20 2a0, 32
100 2a0, 32
20 2a0, 0
20 2a, 91
20 2a, 0
52
68
67
0
2c
3c
4d
5
11
2
The most important issue is to control the competition
between the protonation and halogenation of the vinyl-
silver intermediate. Thus, initial investigations into intra-
molecular haloamination were performed using N-bromo-
succinimide (NBS) as an electrophilic halogen source. To
our delight, treatment of R-aminoallene 1a10 with NBS in
6
NCS/DBU (150)
7
NCS/Et3N (150)
20 2a, 0
6
8
NCS/N-methylimidazole (150)
NCS/pyridine (150)
20 2a, 16
20 2a, 70
20 2a, 91
20 2a, 98
20 2a, 49
20 2a, 3
10 2a, 99 (83)e
20 2a, 33
10 2a, 83
0
9
21
9
10
11
12
13
NCS/2,6-di-tert-butylpyridine (150)
NCS/2,6-lutidine (150)
NCS/K2CO3 (150)
1
0
NCS/NaOtBu (150)
43
1
(6) Other transition metals such as Au, Pd, and Cu were also known
to catalyze the cyclization of R-aminoallenes. Au: (a) Morita, N.;
Krause, N. Org. Lett. 2004, 6, 4121. Pd:(b) Ma, S.; Yu, F.; Gao, W.
J. Org. Chem. 2003, 68, 5943. (c) Dieter, R. K.; Yu, H. Org. Lett. 2001, 3,
3855. (d) Karstens, W. F. J.; Klomp, D.; Rutjes, F. P. J. T.; Hiemstra, H.
Tetrahedron 2001, 57, 5123. (e) Ohno, H.; Toda, A.; Miwa, Y.; Taga, T.;
Osawa, E.; Yamaoka, Y.; Fujii, N.; Ibuka, T. J. Org. Chem. 1999, 64,
2992. (f) Prasad, J. S.; Liebeskind, L. S. Tetrahedron Lett. 1988, 29, 4257.
Cu: see ref 10.
14c NCS/2,6-lutidine (40)
15
chloramine-T/ꢀ
16c N-chlorophthalimide/2,6-lutidine (40)
49
1
a Reaction conditions: R-aminoallene 1a (0.50 mmol), Xþ (0.65
mmol), [Ag(phen)OTf], base, MeCN (4.0 mL), 60 °C, 30 min. b Deter-
mined by 1H NMR spectroscopy. c At 80 °C. d With NBS (2.0 equiv).
e Isolated yield.
(7) On the basis of the similar concept, the gold-catalyzed iodoalk-
oxylation of allene has already been reported, see: Buzas, A.; Istrate, F.;
Gagosz, F. Org. Lett. 2006, 8, 1957.
We further hypothesized that an appropriate base could
temper the reaction acidity and retard the protonation
of the presumed vinyl-silver imtermediate. Therefore, our
next step was to test the effects of base additives.
(8) For examples of the catalytic reaction of N-iodosuccinimide
(NIS) with in situ generated vinyl-gold intermediates, see: (a) Yu, M.;
Zhang, G.; Zhang, L. Org. Lett. 2007, 11, 2147. (b) Kirsch, S. F.; Binder,
J. T.; Crone, B.; Duschek, A.; Haug, T. T.; Liebert, C.; Menz, H. Angew.
Chem., Int. Ed. 2007, 46, 2310. (c) Buzas, A.; Gagosz, F. Org. Lett. 2006,
8, 515. (d) Buzas, A.; Gagosz, F. Synlett 2006, 2727.
ꢀ
(9) 3-Pyrroline units are prominent structural motifs in natural
products, see: (a) Smith, T. A.; Croker, S. J.; Loeffler, R. S. T. Phyto-
chemistry 1986, 2, 683. (b) Anderson, W. K.; Milowsky, A. S. J. Med.
Chem. 1987, 30, 2144.
(10) R-Aminoallenes can be readily prepared by the NHC-Cu-cata-
lyzed selective allenylation of imines, see: Sai, M.; Yorimitsu, H.;
Oshima, K. Angew. Chem., Int. Ed. 2011, 50, 3294. We slightly modified
this procedure for the preparation of R-aminoallene substrates 1. See the
Supporting Information for details.
(11) Carney, J. M.; Donoghue, P. J.; Wuest, W. M.; Wiest, O.;
Helquist, P. Org. Lett. 2008, 10, 3903.
(12) The structure of 2a was unambiguously identified by spectro-
scopic and X-ray crystallographic analyses. See the Supporting Infor-
mation for details.
(13) It should be noted that the use of more electrophilic silver salts
such as AgOTf and AgNO3 led to a mixture of products, in which 2a was
detected in only 20 and 14% NMR yield, respectively.
Org. Lett., Vol. 13, No. 17, 2011
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