Copper-catalyzed intramolecular hydroamination of allenylamines to 3-pyrrolines or 2-alkenylpyrrolidines

Article abstract of DOI:10.1016/j.tetlet.2008.09.003

Copper salts, such as CuCl, CuI, CuCl₂ and Cu(OTf)₂, were used to catalyze the intramolecular hydroamination of allenylamines to provide the corresponding 3-pyrrolines or 2-alkenylpyrrolidines.

Full text of DOI:10.1016/j.tetlet.2008.09.003

Tetrahedron Letters 49 (2008) 6529–6532
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Tetrahedron Letters
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Copper-catalyzed intramolecular hydroamination of allenylamines to
3-pyrrolines or 2-alkenylpyrrolidines
*
Akiko Tsuhako, Daisuke Oikawa, Kazushi Sakai, Sentaro Okamoto
Department of Material and Life Chemistry, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 July 2008
Revised 28 August 2008
Accepted 1 September 2008
Available online 3 September 2008
Copper salts, such as CuCl, CuI, CuCl2 and Cu(OTf)2, were used to catalyze the intramolecular hydro-
amination of allenylamines to provide the corresponding 3-pyrrolines or 2-alkenylpyrrolidines.
Ó 2008 Elsevier Ltd. All rights reserved.
Table 1
Cyclization of allenylamines 1 gives N-heterocycles 2, via an
endo-hydroamination pathway, or 3, via an exo-hydroamination
pathway.1 Many means to catalyze these transformations have
been developed with metal salts or complexes of Ti, Zr,3 lantha-
nides,3 Pd,4 Ag,5 Au6 and Hg7 (Scheme 1).8 Herein disclosed is our
finding that copper (I) and (II) salts, such as CuCl, CuBr, CuI, CuCl2
and Cu(OTf)2 [OTf = OSO2CF3], can effectively catalyze the transfor-
mation of 1 to 3-pyrrolines 2 (n = 0) or 2-alkenylpyrrolidines 3
(n = 2).9
Copper-catalyzed intramolecular hydroamination of allenylamines
Entry
Substrate
CuXn
Product
Yield (%)
1
2
3
4
5
6
7
8
9
CuCl
CuBr
Cul
90
99
98
Trace
99
CuF2
The results for the reaction of c-allenylamine 1a and a-allenyl-
CuCl2
Cu(OTf)2
amine 1b with various copper salts are summarized in entries 1–14
of Table 1. Entries 1–6 show that, except for CuF2, a variety of cop-
per (I) and (II) salts catalyzed the intramolecular hydroamination
of 1a in an exo-cyclization fashion to provide 2-vinylpyrrolidine
3a in excellent yields. Similarly, 1b was effectively cyclized, but
in an endo-fashion, to 3-pyrroline 2b in good to excellent yields
(entries 11–14). The reaction with copper catalysts was faster than
that with AuCl3 but slower than that with AgOTf under the same
conditions (entries 9 and 10). Introduction of ligands, such as
diphosphine (dppe) and N-heterocyclic carbene, to the reaction
with copper salts did not result in any conversion of the substrate
(entries 7 and 8). Among the copper salts that were effective to the
reaction, Cu(OTf)2 catalyzed at the fastest rate. As revealed by en-
tries 15–18, secondary as well as primary amines (1f) were
98
CuXn + dppeb
Trace
Trace
>98
a
lMes-CuClc
(
AgOTf (3 h)
AuCl3 (4 days)
(
10
>98
11
12
13
14
CuCl
Cul
CuCl2
Cu(OTf)2
55
98d
96
96
15
16
17
18
1c: R = p-Ts, R' = H
1d : R = C(O)Ph, R' = H
1e : R = C(O)OBn, R' = Ph
1f: R = H, R' = Ph
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
3c: Trace
3d: Trace
3e: Trace
3f: 88
a
CuI, CuCl or Cu(OTf)2.
1,2-Bis(diphenylphosphino)ethane.
N,N0-Di(2,4,6-trimethylphenyl)imidazol-2-ylidene copper (I) chloride.
b
c
d
15 h.
Scheme 1. Transformation of allenylamines to N-heterocycles.
smoothly cyclized in the presence of copper salts, whereas all
amides tested (1c, 1d and 1e) did not react in this system at all.
* Corresponding author. Tel.: +81 45 481 5661; fax: +81 45 413 9770.
E-mail address: okamos10@kanagawa-u.ac.jp (S. Okamoto).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.003

6530
A. Tsuhako et al. / Tetrahedron Letters 49 (2008) 6529–6532
Other representative examples for the transformation are illus-
reomeric ratios to those of the substrates (entries 2–5). The results
trated in Table 2.10,11 Substrates having an allene-substituent, 1g,
1h and 1i, were cyclized in the presence of Cu(OTf)2 to the corre-
sponding pyrrolidine 3g and 3-pyrrolines 2h and 2i, respectively,
in good yields (entries 1–5). Thus, the reaction of 1g gave 88% of
2-penten-1-ylpyrrolidine 3g with >97% E of olefin geometry. Cycli-
zation of 1h and 1i with CuI or Cu(OTf)2 catalyst afforded the
corresponding 2,5-disubstituted pyrrolidines with similar diaste-
for the cyclization of 1j (entries 6–8) indicate that no epimerization
at the amine
a
position(s) occurred under the reaction conditions.
b-Substituted
a
-allenylamine 1k also smoothly reacted to give 2,3-
disubstituted 3-pyrroline 2k in excellent yield (entry 9). It was ob-
served again that the Cu(OTf)2-catalyzed reaction was much faster
than the reaction with AuCl3 (entries 4 and 10). The catalysis could
be applied to the cyclization of
a-allenylamine having a secondary
Table 2
Other representative examples
Entry
1
Substrate
CuXn
Product
Yield (%)
88
Cu(OTf)2
2
3
(4
5
1h: R = Ph (dr 70:30)a
1h: R = Ph (dr 70:30)a
1h: R = Ph (dr 70:30)a
1i: R = n-Hex (dr 65:35)a
Cul
2h (d.r. 68:32)a,b
2h (d.r. 64:36)a,b
2h (d.r. 68:32)a,b
2i (d.r. 57:43)a
15
89
80)
79
Cu(OTf)2
AuCl3 (5 days)
Cu(OTf)2
6
7
8
1j (dr 95:5)a
1j (dr 95:5)a
1j (dr 95:5)a
Cul
CuCl2
Cu(OTf)2
2j (dr 95:5)a
2j (dr 95:5)a
2j (dr 95:5)a
95
86
88
9
(10
1k
1k
Cu(OTf)2
AuCl3 (4 days)
2k
2k
95
51)
11
Cu(OTf)2
89
12
Cu(OTf)2
Cu(OTf)2
Complex mixture (15 of 1m was recovered)
17c
13
Determined by 1H NMR analysis.
Anti(dl) product was major.
After the reaction for 2 days, 81% of 1n was recovered.
a
b
c

A. Tsuhako et al. / Tetrahedron Letters 49 (2008) 6529–6532
6531
G. Org. Lett. 2002, 4, 1475; (d) Straub, B. F.; Bergman, R. G. Angew. Chem., Int. Ed.
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Am. Chem. Soc. 1992, 114, 1708.
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V. M.; Tian, S.; McDonald, F. E.; Marks, T. J. Organometallics 1999, 18, 1949; (e)
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120, 4871.
4. (a) Pd: L. M. Lutete, I. Kadota, Y. Yamamoto 2004 126 1622.; (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) Kang, S.-K.; Kim, K.-J. Org. Lett. 2001, 3, 511; (e) Karstens, W. F. J.;
Klomp, D.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron 2001, 57, 5123; (f) Ohno,
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Chem. 1999, 64, 2992; (g) Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1998, 39,
5421; (h) Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1999, 121, 10012; Intermolecular
reaction: (i) Al-Masum, M.; Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1997,
38, 6071; (j) Karstens, W. F. J.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron Lett.
1997, 35, 6257; (k) Besson, L.; Goré, J.; Cazzes, B. Tetrahedron Lett. 1995, 36,
3867; (l) Davis, I. W.; Scopes, D. I. C.; Gallagher, T. Synlett 1993, 85; (m) Kimura,
M.; Fugami, K.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1992, 57, 6377; (n) Prasad, J.
S.; Liebeskind, L. S. Tetrahedron Lett. 1988, 29, 4257.
5. Ag: (a) Dieter, R. K.; Chen, N.; Gore, V. K. J. Org. Chem. 2006, 71, 8755; (b)
Amombo, M. O.; Hausherr, A.; Reissig, H.-U. Synlett 1999, 1871; (c) Davis, I. W.;
Gallagher, T.; Lamont, R. B.; Scopes, I. C. J. Chem. Soc., Chem. Commun. 1992, 335;
(d) Kinsman, R.; Lathbury, D.; Vernon, P.; Gallagher, T. J. Chem. Soc., Chem.
Commun. 1987, 243.
Figure 1. Possibility for the reaction mechanism.
6. Au: (a) LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007,
129, 2452; (b) Zhang, Z.; Liu, G.; Kinder, R. E.; Han, Z.; Qian, H.; Widenhoefer, R.
A. J. Am. Chem. Soc. 2006, 128, 9066; (c) Morita, N.; Krause, N. Eur. J. Org. Chem.
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(e) Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121.
N-substituent (entry 11). The reaction of d-allenylamines 1n with
Cu(OTf)2 catalyst proceeded slowly to provide 6-exo-cyclization
product piperidine 3n in 17% yield after 24 h, where 83% of 1n
was recovered. Meanwhile, b-allenylamine 1m reacted faster than
1n, but resulted in the formation of a complex mixture.
Based on the alkene geometry of the product, reaction mecha-
nisms for the exo-cyclization, via the metal-catalyzed intramolecu-
lar hydroamination of allenylamines, have been proposed in the
literatures involving an anti-aminometallation pathway through
a metal-coordinated allenic species a or b (Fig. 1, (i), in which a
is disfavour due to steric repulsion between R and NHR’ groups)
and an syn-aminometallation process through a metal amide inter-
mediate c (Fig. 1, (ii)).1–8 As revealed from the results of the trans-
formation of 1g, the present copper-catalyzed reaction gave 3g
with high selectivity for the E-olefin geometry and, therefore, an
anti-aminometallation pathway (i) may be postulated for the
mechanism.12
In summary, we have demonstrated that the intramolecular
hydroamination of allenylamines to 3-pyrolines or 2-alkenylpyrr-
olidines is effectively catalyzed by various copper salts. These
salts, which exhibited good catalytic reactivity, are inexpensive
and are relatively less-toxic, both of which are characteristics
that should be synthetically useful especially for application to
a large-scale process. More details concerning the stereospecific-
ity of the reaction and its application to asymmetric processes
are underway.
7. Hg Fox, D. N. A.; Lathbury, D.; Mahon, M. F.; Molly, K. C.; Gallagher, T. J. Chem.
Soc., Chem. Commun. 1989, 1073.
8. Pd-catalyzed bromoamination of allenes: (a) Jonasson, C.; Horváth, A.;
Väckvall, J.-E. J. Am. Chem. Soc. 2000, 122, 9600; Ru-catalyzed carboamination
of allens: (b) Trost, B. M.; Pinkerton, A. B.; Kremzow, D. J. Am. Chem. Soc. 2000,
122, 12007; Ta-catalyzed intermolecular hydroamination of allenes: (c)
Anderson, L. L.; Arnold, J.; Bergman, R. G. Org. Lett. 2004, 6, 2519.
9. Cu-catalyzed cyclization of iminoallenes to pyrroles has been reported, see: (a)
Nedolya, N. A.; Brandsma, L.; Tarasova, O. A.; Verkruijsse, H. D.; Trofimov, B. A.
Tetrahedron Lett. 1998, 39, 2409; (b) Brandsma, L.; Nedolya, N. A.; Brandsma, L.;
Tplmachev, S. V. Chem. Heterocycl. Compd. 2002, 38, 745; (c) Brandsma, L.;
Nedolya, N. A.; Tplmachev, S. V. Chem. Heterocycl. Compd. 2002, 38, 54; (d)
Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074. Cu-
catalyzed intermolecular hydroaminaton of active alkenes has been reported,
see:; (e) Taylor, J. G.; Whittall, N.; Hii, K. K. Org. Lett. 2006, 8, 3561; (f) Munro-
Leighton, C.; Delp, S. A.; Blue, E. D.; Gunnoe, T. B. Organometallics 2007, 26,
1483. For Cu-catalyzed hydroamination of multiple bonds, see:; (g) Prior, A. M.;
Robinson, R. S. Tetrahedron Lett. 2008, 49, 411.
10. General procedure: To a solution of allenylamine 1 (0.50 mmol) in CH2Cl2
(1.0 mL) was added a copper salt (0.0025 mmol, 5.0 mol %), and then the
mixture was stirred at ambient temperature. After addition of aqueous
saturated Na2CO3 solution, the mixture was extracted with ether
(2 ꢀ 10 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The
resultant residue was purified by silica gel column chromatography.
Spectroscopic data of 3a and 3n (1H, 13C NMR) were in good agreement with
those reported (Katrizky, A. R.; Yao, J.; Yang, B. J. Org. Chem. 1999, 64, 6066). 1H
NMR data of other products (500 or 600 MHz, CDCl3) d: 2b, 7.10–7.95 (m, 10H),
5.85 (d, J = 4.5 Hz, 1H), 5.72 (d, J = 4.5 Hz, 1H), 4.61 (br s, 1H), 3.97 (d,
J = 13.5 Hz, 1H), 3.75 (dd, J = 4.5, 14.0 Hz, 1H), 3.55 (d, J = 13.5 Hz, 1H), 3.31 (dd,
J = 5.5, 14.0 Hz, 1H); 2h 6.90–7.50 (m, 15H), (for anit, dl) 5.97 (br s, 1H), 4.98 (br
s, 1H), 3.73 (d, J = 14.5 Hz, 1H), 3.25 (d, J = 14.5 Hz, 1H), (for syn, meso) 5.68 (br
s, 1H), 4.85 (br s, 1H), 3.82 (s, 2H); 2i 7.10–7.50 (m, 10H), 1.10–1.70 (m, 10H),
0.88 (t, J = .2 Hz, 3H), (for major) 5.72 (br d, J = 6.0 Hz, 1H), 5.58 (br d, J = 5.4 Hz,
1H), 4.68 (dt, J = 4.8, 2.4 Hz, 1H), 3.92 (d, J = 13.8 Hz, 1H), 3.82 (m, 1H), 3.80 (d,
J = 13.8 Hz, 1H), (for minor), 5.97 (br d, J = 6.6 Hz, 1H), 5.81 (br s, J = 6.0 Hz, 1H),
4.79 (d, J = 5.4 Hz, 1H), 3.69 (m, 1H), 3.81 (d, J = 14.4 Hz, 1H), 3.49 (d,
J = 14.4 Hz, 1H); 2j, 6.90–7.40 (m, 10H), 5.73 (br s, 1H), 5.52 (br s, 1H), 4.80
(br s, 1H), 3.91 (t, J = 5.5 Hz, 1H), 3.61–3.83 (m, 3 H), 3.58 (dd, J = 6.8, 9.6 Hz,
1H), 3.15 (s, 3H); 2k, 7.10–7.45 (m, 15H), 6.31 (dd, J = 2.5, 4.0 Hz, 1H), 5.04 (br
s, 1H), 3.83 (d, J = 13.0 Hz, 1H), 3.82 (ddd, J = 1.5, 5.5, 14.0 Hz, 1H), 3.62 (d,
J = 13.0 Hz, 1H), 3.55 (ddd, J = 1.5, 4.0, 14.0 Hz, 1H); 2l, 7.41 (d, J = 8.0 Hz, 2H),
7.25 (d, J = 8.0 Hz, 2H), 5.80 (d, J = 3.5 Hz, 1H), 5.56 (d, J = 3.5 Hz, 1H), 4.66 (br s,
1H), 3.84 (dd, J = 5.5, 14.5 Hz, 1H), 3.57 (dt, J = 14.5, 3.0 Hz, 1H), 2.86 (hept,
J = 6.0 Hz, 1H), 0.99 (d, J = 6.5 Hz, 3H), 0.96 (d, J = 6.0 Hz, 3H); 3f, 7.04–7.42 (m,
10H), 5.86 (ddd, J = 6.9, 10.3, 17.2 Hz, 1H), 5.12 (d, J = 17.2 Hz, 1H), 4.97 (d,
J = 10.3 Hz, 1H), 3.76 (d, J = 10.9 Hz, 1H), 3.74 (m, 1H), 3.45 (d, J = 10.9 Hz, 1H),
2.75 (ddd, J = 1.7, 6.9, 12.6 Hz, 1H), 2.25 (dd, J = 9.2, 12.6 Hz, 1H); 3g, 7.18–7.34
(m, 5H), 5.61 (dt, J = 14.9, 6.9 Hz, 1H), 5.38 (dd, J = 8.0, 14.5 Hz, 1H), 4.04 (d,
J = 13.2 Hz, 1H), 3.02 (d, J = 13.2 Hz, 1H), 2.92 (t, J = 8.1 Hz, 1H), 2.72 (q,
J = 8.0 Hz, 1H), 2.02–2.10 (m, 3H), 1.93 (m, 1H), 1.57–1.80 (m, 3H), 1.36–1.47
(m, 2H), 0.91 (t, J = 7.5 Hz, 3H).
Acknowledgements
This study was partially supported by the Scientific Frontier
Research Project from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
References and notes
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6532
A. Tsuhako et al. / Tetrahedron Letters 49 (2008) 6529–6532
11. Preparation of allenylamines: Allenylamines 1a, 1c–f, 1m and 1n were prepared
from the corresponding terminal alkynes by treatment with (CH2O)n, (i-Pr)2NH
and CuI. See Refs. 2–6. Compounds 1b and 1h–e were synthesized from imines
12. Production of 2b from 1b by the reaction with 5 mol % of CuI in the presence of
CaH2 (10 mol %) as a proton scavenger could rule out the possibility of the role
of a proton as an actual catalyst.
through the reaction of the corresponding (g
2-imine)Ti(O-i-Pr)2 complexes
with propargyl compounds. See: Fukuhara, K.; Okamoto, S.; Sato, F. Org. Lett.
2003, 5, 2145. For synthesis of 1g, see Ref. 2b.