Cu(I)-catalyzed intramolecular hydroamination of unactivated alkenes bearing a primary or secondary amino group in alcoholic solvents

Article abstract of DOI:10.1021/ol9007712

The Cu-Xantphos system [Cu(O-t-Bu)-Xantphos, 10-15 mol%] catalyzes the intramolecular hydroamination of unactivated terminal alkenes bearing an unprotected aminoalkyl substituent in alcoholic solvents, giving pyrrolidine and piperidine derivatives in exce

Full text of DOI:10.1021/ol9007712

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2145-2147
Cu(I)-Catalyzed Intramolecular
Hydroamination of Unactivated Alkenes
Bearing a Primary or Secondary Amino
Group in Alcoholic Solvents
Hirohisa Ohmiya, Toshimitsu Moriya, and Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido UniVersity,
Sapporo 060-0810, Japan
sawamura@sci.hokudai.ac.jp
Received April 9, 2009
ABSTRACT
The Cu-Xantphos system [Cu(O-t-Bu)-Xantphos, 10-15 mol %] catalyzes the intramolecular hydroamination of unactivated terminal alkenes
bearing an unprotected aminoalkyl substituent in alcoholic solvents, giving pyrrolidine and piperidine derivatives in excellent yields. This
system is applicable to both primary and secondary amines and tolerates a variety of functional groups.
Metal-catalyzed intramolecular hydroamination of alkenes
is one of the simplest methods for the preparation of nitrogen
heterocycles.1Recent research in the intramolecular hy-
droamination of alkenes has pursued the establishment of a
universal hydroamination methodology. However, the de-
velopment of a catalytic system applicable to the addition
of primary or secondary amines to unactivated alkenes
remains an interesting challenge. Various catalysts that
involve different metals have been developed. Lanthanide
and group 4 metal complexes catalyze the hydroamination
with superb efficiency.2 However, the poor functional group
compatibility and high air- and moisture-sensitivity of these
metal complexes have limited their synthetic utility. Recently,
some complexes incorporating precious metals such as Rh,3a,e
Pt,3b,c and Ir3d,e have been introduced as catalysts for the
intramolecular hydroamination of unactivated alkenes bearing
an amino group. Although these catalysts exhibited excellent
(1) For reviews on the hydroamination of alkenes and alkynes, see: (a)
Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675–703. (b) Mu¨ller, T. E.;
Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. ReV. 2008, 108,
3795–3892.
(2) For selected papers on intramolecular hydroaminations of alkenes
catalyzed by lanthanide and group 4 metal complexes, see: (a) Hong, S.;
Marks, T. J. Acc. Chem. Res. 2004, 37, 673–686. (b) Stubbert, B. D.; Marks,
T. J. J. Am. Chem. Soc. 2007, 129, 4253–4271. (c) Bexrud, J. A.; Beard,
J. D.; Leitch, D. C.; Schafer, L. L. Org. Lett. 2005, 7, 1959–1962. (d)
Gribkov, D. V.; Hultzsch, K. C. Angew. Chem. Int. Ed. 2004, 43, 5542–
5546. See also ref 1.
(4) For hydroaminations and hydroamidations of (activated) alkenes
catalyzed by Cu or Fe, see the following. Cu: (a) Taylor, J. G.; Whittall,
N.; Hii, K. K. Org. Lett. 2006, 8, 3561–3564. (b) Munro-Leighton, C.; Delp,
S. A.; Blue, E. D.; Gunnoe, T. B. Organometallics 2007, 26, 1483–1493.
(c) Munro-Leighton, C.; Delp, S. A.; Alsop, N. M.; Blue, E. D.; Gunnoe,
T. B. Chem. Commun. 2008, 111–113. Fe: (d) Komeyama, K.; Morimoto,
T.; Takaki, K. Angew. Chem., Int. Ed. 2006, 45, 2938–2941.
(3) For late transition metal catalyzed intramolecular hydroamination
of unactivated alkenes with alkylamines, see the following. Rh: (a) Liu,
Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 1570–1571. Pt: (b) Bender,
C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070–1071. (c)
Bender, C. F.; Hudson, W. B.; Widenhoefer, R. A. Organometallics 2008,
27, 2356–2358. Ir: (d) Hesp, K. D.; Stradiotto, M. Org. Lett. 2009, 11,
1449–1452. Ir and Rh: (e) Bauer, E. B.; Andavan, G. T. S.; Hollis, T. K.;
Rubio, R. J.; Cho, J.; Kuchenbeiser, G. R.; Helgert, T. R.; Letko, C. S.;
Tham, F. S. Org. Lett. 2008, 10, 1175–1178.
(5) For Pd, see: (a) Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc.
2006, 128, 4246–4247. For Au, see: (b) Zhang, J.; Yang, C.-G.; Chuan, C.
J. Am. Chem. Soc. 2006, 128, 1798–1799. See also ref 1.
10.1021/ol9007712 CCC: $40.75
Published on Web 04/20/2009
 2009 American Chemical Society

functional group compatibility, there still remains room for
further investigation. Specifically, the development of hy-
droamination using a cheap and environmentally benign
metal catalyst is greatly anticipated.4 To date, most of the
investigations on the intramolecular hydroamination of
alkenes catalyzed by late transition metals have focused on
the use of amides or carbamates bearing electron-withdraw-
ing N-substituents such as Ts, Cbz, Boc, or Ac groups instead
of free amines.5
Here we report the intramolecular hydroamination of
unactivated alkenes catalyzed by a Cu-phosphine system.4,6-8
Several aspects of this transformation are noteworthy: (i) Cu,
which is a relatively abundant metal in the earth crust and
hence cheap and environmentally benign, is used as the
metal; (ii) alcoholic solvents are used;7 (iii) both secondary
and primary amines can be used; (iv) not only pyrrolidine
but also piperidine derivatives are obtained; (v) a variety of
functional groups are tolerated; and (vi) olefinic side products
due to ꢀ-hydride elimination or alkene isomerization are not
formed, and the yields are generally high.
Our ligand screening has identified Xantphos, which
features an extraordinary large bite-angle, to be the best,
while the ligand effect was moderate.11 Even without the
ligand, the hydroamination of 1aa proceeded in 49% NMR
yield under essentially the same conditions. Nitrogen-based
ligands such as 1,10-phenanthroline reduced the activity of
the catalyst (20% NMR yield).
Analogues (1ab-ag, 1ba-be) of aminopentene 1aa
bearing different N-substituents were transformed into the
corresponding pyrrolidine derivatives (2ab-ag, 2ba-be)
smoothly at higher temperatures (100 or 140 °C) in a mixed
solvent (MeOH/toluene or MeOH/o-xylene) (Table 1, entries
Table 1. Cu(I)-Catalyzed Hydroamination of Unactivated
Alkenes Bearing Secondary Amino or Amido Groupsa
The reaction of ω-alkenic secondary amine 1aa in the
presence of Cu(O-t-Bu) (10 mol %) and Xantphos (10 mol
%) in MeOH (1 mL) proceeded at 60 °C and afforded the
pyrrolidine derivative 2aa in 80% yield (97% NMR yield)
after 18 h reaction time (Scheme 1).
Scheme 1
.
Cu(I)-Catalyzed Intramolecular Hydroamination of
Aminoalkene 1aa
The employment of the alcoholic solvent MeOH had a
significant impact on the yield of 2aa.9 The use of other
solvents such as toluene, hexane, THF, dioxane, CH3CN,
acetone, DMF, and DMSO resulted in lower yields of 2aa
(0-19% NMR yields). The effectiveness of the protic solvent
would imply a tolerance of this reaction toward a wide
variety of functional groups. Furthermore, its crucial role in
the rate acceleration is of considerable interest from a
mechanistic viewpoint.7,8,10
a Conditions: Cu(O-t-Bu)-Xantphos (10 mol %), 1 (0.5 mmol), MeOH/
toluene (1:1, 1.0 mL), 100 °C or MeOH/o-xylene (1:1, 1.0 mL), 140 °C.
b Isolated yield. c Conditions: Cu(O-t-Bu)-Xantphos (15 mol %), 1 (0.5
mmol), MeOH/toluene (1:1, 1.0 mL), 100 °C or MeOH/o-xylene (1:1, 1.0
mL), 140 °C. d The isolated product was contaminated with a small amount
of 1af (5%).
1-11). Thus, alkyl substituents such as Et, n-Pr, i-Bu, and
2-phenethyl groups were tolerated at the nitrogen atom
(entries 1-4). Amide substrates 1af and 1ag, bearing
electron-withdrawing N-substituents such as acetyl or benzoyl
groups, also underwent hydroamidation in high yields (entries
5 and 6). Although the aminopentene (1ba) with an N-benzyl
group was less reactive than 1aa-ae, the reaction of this
substrate also proceeded smoothly and led to completion with
15 mol % catalyst loading (entry 7). Notably, functionalities
such as methoxy, fluoro, cyano, and ester were tolerated on
the aromatic ring of the N-benzyl group (reactions of
1bb-be, entries 8-11).
(6) For Cu-catalyzed enantioselective intramolecular carboamination and
aminooxygenation of unactivated alkenes, see: (a) Zeng, W.; Chemler, S. R.
J. Am. Chem. Soc. 2007, 129, 12948–12949. (b) Fuller, P. H.; Kim, J.-W.;
Chemler, S. R. J. Am. Chem. Soc. 2008, 130, 17638–17639
.
(7) For Cu-catalyzed addition of terminal alkynes to aldehydes with
alcoholic solvents, see: (a) Asano, Y.; Hara, K.; Ito, H.; Sawamura, M.
Org. Lett. 2007, 9, 3901–3904. (b) Asano, Y.; Hara, K.; Ito, H.; Sawamura,
M. Organometallics 2008, 27, 5984–5996
.
(8) For related studies from our group, see: (a) Ito, H.; Watanabe, A.;
Sawamura, M. Org. Lett. 2005, 7, 1869–1871. (b) Ito, H.; Kawakami, C.;
Sawamura, M. J. Am. Chem. Soc. 2005, 127, 16034–16035. (c) Ito, H.; Ito,
S.; Sasaki, Y.; Matsuura, K.; Sawamura, M. J. Am. Chem. Soc. 2007, 129,
14856–14857. (d) Ito, H.; Kosaka, Y.; Nonoyama, K.; Sasaki, Y.; Sawamura,
M. Angew. Chem., Int. Ed. 2008, 47, 7424–7427. (e) Ito, H.; Sasaki, Y.;
Sawamura, M. J. Am. Chem. Soc. 2008, 130, 15774–15775
.
(9) For details of the solvent effect, see Supporting Information.
(11) DPPF was as effective as Xantphos at 60 °C, while slightly less
effective at 40 °C. For details of the ligand effect, see Supporting
Information.
(10) Yamamoto, Y.; Kirai, N.; Harada, Y. Chem. Commun. 2008, 2010–
2012
.
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Org. Lett., Vol. 11, No. 10, 2009

The diphenylmethylene insert of the aminoalkene 1aa
could be replaced with a cyclohexane-1,1-diyl group without
affecting the reactivity toward the hydroamination (reaction
of 1c, Table 1, entry 12). Unfortunately, however, the
substrate without substituents in the linker chain, where the
Thorpe-Ingold effect does not work, resisted the reaction.
The 1,1-disubstituted alkene 1d also underwent hydroami-
nation under more forcing conditions (15 mol % of Cu, 140
°C) (Table 1, entry 13). Conversely, the addition to a 1,2-
disubstituted alkene did not proceed at all.
A possible mechanism for the Cu-catalyzed intramolecular
hydroamination is proposed in Scheme 2.7,8 The catalytic
Scheme 2. Proposed Mechanism
The extension of the Cu-catalyzed hydroamination from
a five- to six-membered ring formation was feasible, as was
the case with the other catalyst systems reported previously.
Thus, the reaction of 1-amino-5-hexene derivatives 1e and
1f occurred within 24 h at 100 °C to give the corresponding
piperidine derivatives (2e and 2f) in excellent yields (Table
1, entries 14 and 15).1
The Cu catalyst system was also effective for the reaction
of ω-alkenic primary amines (1g-j) (Table 2). In fact, the
cycle would be initiated by σ-bond metathesis between
alkoxycopper A and the H-N bond of the substrate (1) to
form copper amide B. Subsequently, the terminal alkene
coordinates to the Cu atom to form Cu-alkene π-complex
C. Next, the addition of the Cu-N bond across the C-C
double bond affords alkylcopper intermediate D with a
nitrogen heterocycle. Finally, protonolysis of the Cu-C bond
of D with MeOH gives the final product (2). According to
this mechanism, the protonation of D should be much faster
than the ꢀ-hydride elimination to form enamine 3 and copper
hydride E.
Table 2. Cu(I)-Catalyzed Hydroamination with Primary
Aminoalkenes 1g-ja
In summary, the Cu-Xantphos system catalyzed the
intramolecular hydroamination of unactivated terminal alk-
enes bearing an unprotected aminoalkyl substituent in
alcoholic solvents, giving pyrrolidine and piperidine deriva-
tives in excellent yields. This system is applicable to both
primary and secondary amines and tolerates a variety of
functional groups. We believe that this is a significant step
toward economically advantageous and environmentally
benign alkene hydroaminations. Further studies to find more
efficient catalyst systems based on copper are underway.
a Conditions: Cu(O-t-Bu) (0.05-0.075 mmol), Xantphos (1 equiv to
Cu), 1 (0.5 mmol), MeOH/toluene (1:1, 1.0 mL), 100 °C, 72 h. b Isolated
yield. c The isolated yield was reduced by the volatility of the product.
reaction of 1g-j to form five- and six-membered rings in
the presence of 10 or 15 mol % of Cu(I)-Xantphos catalyst
proceeded at 100 °C, delivering the corresponding NH-free
cyclic secondary amines (2g-j) in high yields. It should be
noted that the late transition metal catalyzed intramolecular
hydroamination of unactivated alkenes bearing a primary
amino group has been achieved in only the cases with the
Rh catalyst,3a whereas various catalysts have been used for
the additions of amides and carbamates, where the nitrogen
moieties require installation and removal of the electron-
withdrawing group.4
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Government
of Japan.
Supporting Information Available: Experimental pro-
cedures and NMR spectra for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL9007712
Org. Lett., Vol. 11, No. 10, 2009
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