An in situ generated samarium complex as a practical catalyst for the efficient intramolecular hydroamination of non-activated alkenes

Article abstract of DOI:10.1016/j.tetlet.2008.06.053

Mixing SmI₂ and NaN(TMS)₂ generates in situ an efficient catalyst that promotes the intramolecular hydroamination of non-activated olefins. A wide range of aminoolefins can be cyclised smoothly using this simple protocol. Mechanistic studies led to the identification of the putative active catalyst.

Full text of DOI:10.1016/j.tetlet.2008.06.053

Tetrahedron Letters 49 (2008) 5032–5035
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An in situ generated samarium complex as a practical catalyst for the
efficient intramolecular hydroamination of non-activated alkenes
*
Coralie Quinet, Ali Ates , István E. Markó
Université catholique de Louvain, Département de Chimie, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Mixing SmI2 and NaN(TMS)2 generates in situ an efficient catalyst that promotes the intramolecular
hydroamination of non-activated olefins. A wide range of aminoolefins can be cyclised smoothly using
this simple protocol. Mechanistic studies led to the identification of the putative active catalyst.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 25 April 2008
Revised 2 June 2008
Accepted 10 June 2008
Available online 14 June 2008
Nitrogen-containing compounds form a prominent family of
substances which often display interesting biological activities.
During the past 50 years, numerous synthetic methods have been
developed to address the selective synthesis of amines and their
derivatives.1
The most attractive approach is the direct hydroamination of
olefins, which is defined as the formal addition of an N–H bond
across a carbon–carbon unsaturation. Interestingly, this environ-
mentally benign and optimally atom-economical process often
uses readily available starting materials and generates little or no
by-products. However, despite extensive and elegant contribu-
tions, only limited success has been obtained so far in the develop-
Rare earth metal catalysts have proven to be particularly com-
petent catalysts in various hydroamination reactions.7 Used in
small quantities, they provide the desired amines in good yields
and under mild conditions. However, most of these lanthanide
complexes are difficult to synthesise and to handle, and their prep-
aration often requires specialised and expensive equipment. The
extreme sensitivity of these catalysts towards moisture, oxygen
and various nucleophiles significantly restricts their use in syn-
thetic organic chemistry.
We were intrigued by the possibility of generating in situ a lan-
thanide-based catalyst that could efficiently promote intramolecu-
lar hydroamination reactions. In this manner, we would avoid the
synthesis and the handling of such delicate species altogether. In
this Letter, we report our initial results on the successful imple-
mentation of such a strategy. During the optimisation studies of
the n-BuLi-catalysed hydroamination process, the effect of various
bases, such as LDA, LiHMDS and NaHMDS was investigated. Whilst
ment of
a mild, efficient and practical procedure for the
hydroamination of terminal, non-activated alkenes.2
Our laboratory has recently been interested in the development
of new methodologies for the intramolecular hydroamination of
olefins, and we have previously disclosed a competent and conve-
nient synthesis of cyclic amines using catalytic amounts of n-butyl-
lithium.3 More recently, the scope of this methodology has been
broadened to enable the construction of more complex alkaloid-
like substructures and the direct, one-step, assembly of bicyclic
amines from linear precursors has been reported.4
Apart from the alkali metals, a wide variety of transition metal
promoters have also been used in hydroamination reactions.
Unfortunately, stoichiometric quantities of these complexes are
generally required, rendering this method expensive and of little
practicability. Moreover, modest selectivities in favour of the
hydroaminated product are often observed.5
the addition of LDA to the
x-unsaturated amine 1 afforded
smoothly pyrrolidine 2, the use of LiHMDS or its sodium counter-
part led to no detectable transformation (Fig. 1, entries 1 and 2).
Interestingly, addition of a small amount of SmI2 (10 mol %) to
the NaHMDS solution resulted in the smooth conversion of 1 into
2 (entry 3). To verify that both partners were required, the cyclisa-
tion of 1 was attempted in the presence of SmI2 alone. As expected,
no reaction was observed under these conditions (entry 4). It thus
transpires that mixing a solution of SmI2 (0.1 M in THF) with a
solution of sodium hexamethyldisilazide (2 M in THF) in a 1:2 ratio
leads to the in situ generation of an active hydroaminating catalyst.
Preliminary experiments revealed that a 10 mol % loading of
samarium (from SmI2) is enough to promote the cyclisation of a
Recent breakthroughs in this area involved the successful appli-
cation of catalytic quantities of, i.e. Pd, Pt, Ti, Sc, Zr and Au to the
intramolecular cyclisation of various
x
-unsaturated amines.6
variety of x-unsaturated primary amines, as illustrated in Table 1.
As can be seen, this method provides an easy and efficient
access to pyrrolidines (Table 1, entries 1–4) as well as piperidines
(Table 1, entry 5) in excellent yields. In all cases, complete conver-
sion of the starting amines was observed. As anticipated, the intro-
duction of conformational constraints such as a gem-dimethyl or
* Corresponding author. Tel.: +32 10 478 773; fax: +32 10 472788.
E-mail address: marko@chim.ucl.ac.be (I. E. Markó).
Present address: UCB-Pharma SA Chemical Research, Chemin du Foriest, B-1420
Braine l’Alleud, Belgium.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.053

C. Quinet et al. / Tetrahedron Letters 49 (2008) 5032–5035
5033
SmI2/THF +
NaN(TMS)2/THF
NH2
HN
2
1
Sm(N(TMS)2)2
11
NH2
12
Entry
Base
Additive
Yield
[%]
n
1
2
85
0
LDA 10%
/
H
NaHMDS 20%
NaHMDS 20%
/
n
N
[Sm]
SmI2 10%
3
4
87
0
n
H
N
13
15
SmI2 10%
/
σ-metathesis
Figure 1.
NH2
n
H
N
n
12
Table 1
[Sm]
14
Entry
Substrate
Product
Time (h)
Yielda (%)
85
Figure 2.
NH2
HN
1
2
100
3
1
4
ation in the presence of excess starting amine would then com-
plete the catalytic cycle (Fig. 2).9
In order to broaden the scope of this method, the synthesis of
bicyclic amines was attempted using the in situ generated catalyst.
Unfortunately, cyclisation of substrates 17 provided only traces of
the desired products 18 (Fig. 3, conditions (a)). To our surprise,
NH2
NH2
HN
HN
24
24
87
93
2
10
when a commercial solution of Sm[N(TMS)2]3 was employed,
complete conversion to the fused bicycles 18 was observed. In
the case of pyrrolizidine 18 (n = 1), a single diastereoisomer was
obtained in excellent yield, after 24 h in THF at 60 °C (Fig. 3, condi-
tions (b)).
These results suggest that the active catalyst may actually be a
Sm(III) species and not, as we originally assumed, a Sm(II) deriva-
tive.11 In accord with this assumption, when precursor 17 (n = 1)
was treated with SmI3 and 3 equiv of NaN(TMS)2 (Fig. 3, conditions
(c)), a similarly smooth transformation took place and 18 (n = 1)
was generated quantitatively.12
However, the successful cyclisation of the substituted piperi-
dine 17 (n = 2) into the corresponding indolizidine 18 (n = 2)
required the use of higher temperature. Performing this hydro-
amination reaction in THP/toluene (1:1, v/v) at 110 °C (an efficient
set of conditions that we discovered during our work on the
n-BuLi-catalysed intramolecular hydroamination of non-activated
alkenes4), and using Sm[N(TMS)2]3 as the catalyst, afforded the
desired fused bicyclic adduct 18 (n = 2, Fig. 3, conditions (d)) in
good yield. Indolizidine 18 was obtained as a 1.2:1 mixture of
diastereoisomers in favour of the cis-isomer.
These conditions were then applied successfully to other sub-
strates, such as compound 19, which provided pyrrolidine 20 in
excellent yields and moderate diastereoisomeric ratios (the major
diastereoisomer was shown to possess trans relative stereochemis-
try) (Fig. 4).
3
4
5
6
NH2
HN
6
93
88
7
9
8
H
N
NH2
5
24
10
a
All yields are for pure, isolated compounds. All the conversions are quantitative
and the reactions are performed using 10 mol % SmI2 (0.1 M in THF) and 20 mol %
NaN(TMS)2 (2 M in THF) in THF (0.5 M solutions) at 60 °C.
cyclohexyl substituent (Table 1, entries 2 and 3) leads to consider-
ably shorter reaction times.
Using this in situ generated catalytic system, the synthesis of
piperidine 10 (Table 1, entry 5) from the aminoolefin 9 could be
accomplished in excellent yield. It is noteworthy that in this case,
the Thorpe-Ingold effect played a major role. Indeed, in the absence
of the gem-dimethyl substituent, no piperidine product could be
obtained.
At this stage of our investigations, a mechanistic hypothesis was
proposed, largely inspired by the seminal results obtained by
Marks and co-workers (Fig. 2).8
Thus, it was envisioned that the addition of SmI2 to NaN(TMS)2
might lead to the in situ formation of the Sm(II) complex 11. Sub-
Finally, this methodology was applied to a short synthesis of
( )-dihydropinidine 22. As shown in Figure 5, addition of
10 mol % of Sm[N(TMS)2]3 to the aminoolefin 21, in THP, at 90 °C,
smoothly led to ( )-22 in excellent yield and good diastereo-
isomeric ratio (Fig. 5).
sequent
r
-metathesis with the aminoolefin 12 would then gener-
In summary, we have developed an efficient synthesis of nitro-
gen heterocycles based upon a novel protocol involving the intra-
molecular hydroamination of olefins promoted by catalytic
ate the amino-samarium complex 13. Insertion of the nitrogen–
metal bond into the pendent unsaturation, followed by proton-

5034
C. Quinet et al. / Tetrahedron Letters 49 (2008) 5032–5035
H
N
N
H
n
n
17
18
Conditions
n = 1
n = 2
SmI2 0.1 M / THF (10 mol%)
NaN(TMS)2 2 M / THF (20 mol%)
THF, 60 ˚C, 48 h
(a)
6% conv.
0%
0%
Sm[N(TMS)2]3 (10 mol%)
THF, 60 ˚C, 24 h
(b)
(c)
100% conv.
86% yield
SmI3 (10 mol%)
NaN(TMS)2 2 M / THF (30 mol%)
Toluene, 100 ˚C, 24 h
100% conv.
100% conv.
61% yield
Sm[N(TMS)2]3 (10 mol%)
THP/Toluene 1:1, 110 ˚C, 24 h
(d)
Figure 3.
Acknowledgements
H
NH
H
N
Financial support of this work by the Université catholique de
Louvain and Merck Sharp and Dohme (Merck Academic Develop-
ment Program Award to IEM) is gratefully acknowledged.
19
20
Sm[N(TMS)2]3 (10 mol%) 100% conv.
(a)
THF, 60 ˚C, 24 h
95% yield
d.r.= 2.6:1
References and notes
1. (a) Smith, P. A. S. The Chemistry of Open-Chain Organic Nitrogen Compounds;
Benjamin W. A., 1965; (b) Patai, S. The Chemistry of The Functional Groups, The
Chemistry of The Amino Group; Interscience, 1968; (c) Brown, B. R. The Organic
Chemistry of Aliphatic Nitrogen Compounds; Oxford (University Press): England,
1994; (d) Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. Adv. Synth. Catal. 2002,
344, 795.
2. For general references on hydroamination, see: (a) Gasc, M. B.; Lattes, A.; Perie,
J. J. Tetrahedron 1983, 39, 703; (b) Steinborn, D.; Brunet, J.-J.; Neibecker, D.;
Niedercorn, F. J. Mol. Catal. 1989, 49, 235; (c) Roundhill, D. M. Chem. Rev. 1992,
92, 1; (d) Müller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675; (e) Brunet, J.-J.;
Neibecker, D. In Catalytic Heterofunctionalization; Togni, A., Grützmacher, H.,
Eds.; Wiley-VCH, 2001; Chapter 4; p 91; (f) See Ref 1; (g) Molander, G. A.;
Romero, J. A. C. Chem. Rev. 2002, 102, 2161; (h) Pohlki, F.; Doye, S. Chem. Soc.
Rev. 2003, 32, 104; (i) Hartwig, J. F. Pure Appl. Chem. 2004, 76, 507; (j) Hong, S.;
Marks, T. J. Acc. Chem. Res. 2004, 37, 673.
SmI3 (10 mol%)
NaN(TMS)2 2 M / THF
(30 mol%)
(b)
100% conv.
73% yield
d.r.= 3.2:1
Toluene, 100 ˚C, 24 h
Figure 4.
Sm[N(TMS)2]3
(10 mol%)
N
N
H2
H
3. Ates, A.; Quinet, C. Eur. J. Org. Chem. 2003, 1623.
21
22
4. Quinet, C.; Jourdain, P.; Hermans, C.; Ates, A.; Lucas, I.; Markó, I. E. Tetrahedron
2008, 64, 1077.
46% conv.
THF, 60 ˚C, 24 h
THP, 90 ˚C, 24 h
5. For hydroamination of alkenes mediated by transition metals, see: (a) Stern, E.
W.; Spector, M. L. Proc. Chem. Soc. London 1961, 370; (b) Coulson, D. R.
Tetrahedron Lett. 1971, 429; (c) Akermark, B.; Bäckvall, J. E.; Hegedus, L. S.;
Zetterberg, K.; Siirala-Hansen, K.; Sjöberg, K. J. Organomet. Chem. 1974, 72, 127;
(d) Gasc, M. B.; Lattes, A.; Perie, J. J. Tetrahedron 1978, 34, 1943; (e) See Ref. 2a;
(f) Brunet, J.-J.; Neibecker, D.; Philippot, K. Tetrahedron Lett. 1993, 34, 3877.
6. See, for example: (a) Gribkov, D. V.; Hultzsch, K. C. Angew. Chem., Int. Ed. 2004,
43, 5542; (b) Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 4391; (c) Bender, C. F.;
Widenhoefer,R. A. J. Am. Chem. Soc. 2005, 127, 1070; (d) Han, X.; Widenhoefer,
R. A. Angew. Chem., Int. Ed. 2006, 45, 1747; (e) Bexrud, J. A.; Beard, J. D.; Leitch,
D. C.; Schafer, L. L. Org. Lett. 2005, 7, 1959; (f) Michael, F. E.; Cochran, B. M. J. Am.
Chem. Soc. 2006, 128, 4246; (g) Zhang, J.; Yang, C.-G. ; He, C. J. Am. Chem. Soc.
2006, 128, 1798; (h) Müller, C.; Loos, C.; Schulenberg, N.; Doye, S. Eur. J. Org.
Chem. 2006, 2499; (i) Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig, J.
F. J. Am. Chem. Soc. 2006, 128, 1828.
7. For selected references on lanthanide and actinide-catalysed hydroaminations,
see: With metallocene Ln catalysts: (a) Gagné, M. R.; Nolan, S. P.; Marks, T. J.
Organometallics 1990, 9, 1716; (b) Molander, G. A.; Dowdy, E. D. J. Org. Chem.
1998, 63, 8983; (c) Ryu, J.-S.; Li, G. Y.; Marks, T. J. J. Am. Chem. Soc. 2003, 125,
12584; (d) Molander, G. A.; Pack, S. K. J. Org. Chem. 2003, 68, 9214; (e) Stubbert,
B. D.; Marks, T. J. J. Am. Chem. Soc. 2007, 129, 4253; With biphenolate and
binaphtholate Ln catalysts: (f) Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. J. Am.
Chem. Soc. 2006, 128, 3748; (g) Yu, X.; Marks, T. J. Organometallics 2007, 26, 365;
With diamine/diamide Ln catalysts: (h) Kim, Y. K.; Livinghouse, T.; Bercaw, J. E.
100% conv.
82% yield
d.r.= 5.7:1
Figure 5.
amounts of an in situ generated samarium complex, obtained by
mixing SmI2 (10 mol %) with NaN(TMS)2 (20 mol %). This method
has initially allowed us to prepare various, substituted pyrrol-
idines. Subsequently, the nature of the active catalytic species
has been revealed as being a Sm(III) complex and not the expected
Sm(II) derivative, thereby enabling the use of commercially avail-
able Sm[N(TMS)2]3. With this catalyst, we have been able to extend
the scope of our methodology by successfully performing the
synthesis of several piperidines and some fused bicyclic amines.13
The usefulness of our method was demonstrated through a short
synthesis of ( )-dihydropinidine.

C. Quinet et al. / Tetrahedron Letters 49 (2008) 5032–5035
Tetrahedron Lett. 2001, 42, 2933; (i) Kim, Y. K.; Livinghouse, T. Angew. Chem., Int.
Ed. 2002, 41, 3645; (j) Roesky, P. W.; Muller, T. E. Angew. Chem., Int. Ed. 2003, 42,
2708; (k) Hultzsch, K. C.; Hampel, F.; Wagner, T. Organometallics 2004, 23,
2601; (l) Kim, Y. K.; Livinghouse, T. Org. Lett. 2005, 7, 1737; (m) Riegert, D.;
Collin, J.; Meddour, A.; Schultz, E.; Trifonov, A. J. Org. Chem. 2006, 71, 2514; (n)
Rastätter, M.; Zulys, A.; Roesky, P. W. Chem. Eur. J. 2007, 13, 3606.
5035
9
H
1
N
2
8
5
6
3
4
7
8. (a) Gagné, M. R.; Marks, T. J. J. Am. Chem. Soc. 1989, 111, 4108; (b) Gagné, M. R.;
Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1992, 114, 275; (c) Motta, A.; Lanza, G.;
Fragala‘, I. L.; Marks, T. J. Organometallics 2004, 23, 4097; (d) Motta, A.; Fragala‘,
I. L.; Marks, T. J. Organometallics 2006, 25, 5533.
solution of NaCl, dried over MgSO4 and the solvent was removed carefully in
vacuo, at 0 °C. Vacuum transfer (1.5 mbar, rt) gave 439 mg of pure 2,5,5-
trimethylpiperidine 10 (88% yield) as a colourless oil.
9. It is interesting to note that the presence of a hydrogen atom on the nitrogen of
1H NMR (300 MHz, CDCl3) dH (ppm): 2.62–2.40 (3H, m, H-2 and H-8), 1.48–
1.12 (4H, m, H-3 and H-4), 1.06 (3H, d, J = 6.3 Hz, H-1), 0.95 (3H, s) and 0.83
(3H, s) (H-6 and H-7). 13C NMR (50 MHz, CDCl3) dC (ppm): 58.9 (C-8), 52.5 (C-
2), 38.2 and 31.4 (C-3 and C-4), 29.6 (C-5), 29.5, 23.9 and 22.9 (C-1, C-6 and C-
7). MS (CI, 70 eV) m/z (relative intensity, %): 128 (M+1, 34), 69 (53), 55 (100),
complex 13 appears to play
a crucial role in the success of these
hydroamination reactions. Indeed, attempted cyclisation of the secondary
aminoolefin 16, under the optimal conditions developed for the primary
amines, did not yield the corresponding piperidine adduct, even after 20 h.
41 (82). IR (KBr)
[141511-51-5].
Preparation of 18 (n = 1) using Sm[N(TMS)2]3
m
(cmÀ1): 3299 [m], 2953–2855 [s], 1459 [m], 1379 [m]. CAS:
SmI2 0.1 M / THF
(10 mol%)
In a flame-dried Schlenk apparatus, maintained under a positive pressure of
argon, a solution of aminoolefin 17 (n = 1) (100 mg, 0.80 mmol, 1 equiv) in
tetrahydrofuran (1.6 ml, 0.5 M) was added, at room temperature, to
Sm[N(TMS)2]3 (solid, 50 mg, 0.080 mmol, 10 mol %). The resulting solution
was stirred and heated at 60 °C for 24 h. The corresponding pyrrolizidine 18
(n = 1) was obtained following the same work-up and purification method as
described above (86 mg, 86% yield).
NaN(TMS)2 2 M / THF
(20 mol%)
H
N
Ph
No reaction
THF, 60 ˚C, 20 h
16
10. (a) Bürgstein, M. R.; Berberich, H.; Roesky, P. W. Chem. Eur. J. 2001, 7, 3078; (b)
Hultzsch, K. C.; Gribkov, D. V.; Hampel, F. J. Organomet. Chem. 2005, 4441.
1
11. In some experiments using the first-generation catalytic system,
a
2
3
characteristic colour change of the mixture (from blue to yellow) was
occasionally observed without detrimental effect on the efficiency of the
reaction.
N
6
8
7
4
5
12. For solubility reasons, SmI3, a yellow solid, was initially dissolved in toluene.
Then, a THF solution of NaN(TMS)2 was added, followed by the aminoolefin.
Using this protocol, results similar to those obtained under conditions (b) could
be achieved after 24 h at 100 °C.
H
1H NMR (500 MHz, CDCl3) dH (ppm): 3.61 (1H, quint, J = 7.0 Hz, H-5), 2.98–2.91
(1H, m, H-2), 2.68–2.57 (2H, m, H-8), 2.06–1.98 (1H, m), 1.97–1.80 (4H, m) and
1.54–1.32 (3H, m) (H-3, 4, 6 and 7), 1.13 (3H, d, J = 6.2 Hz, H-1).13C NMR
(125 MHz, CDCl3) dC (ppm): 65.0 (C-5), 62.3 (C-2), 53.5 (C-8), 35.8 (C-3), 33.1
(C-6), 32.4 (C-4), 25.9 (C-7), 21.2 (C-1). MS (EI, 70 eV) m/z (relative intensity,
%): 125 (M+Å, 6), 124 (53), 110 (17), 108 (43), 105 (15), 97 (36), 96 (24), 91 (16),
83 (28), 82 (56), 80 (57), 77 (61), 70 (26), 69 (100), 67 (35), 65 (20), 55 (67), 53
(22), 51 (18). IR (film)
1381 [m], 1356 [m], 1090 [w], 1036 [w], 800 [w], 702 [w]. CAS: [19451-50-4]
cis-(S,S).
13. Preparation of 10 using commercial solutions of SmI2 and NaN(TMS)2
In
solution of SmI2, 0.1 M, in THF (3.9 ml, 0.393 mmol, 10 mol %) was added to a
stirred solution of 1-amino-2,2-dimethylhex-5-ene (500 mg, 3.93 mmol,
a flame-dried Schlenk apparatus, maintained at room temperature, a
9
1 equiv) in tetrahydrofuran (3.5 ml, 0.5 M). Then, a solution of NaN(TMS)2, 2 M,
in THF (0.4 ml, 0.786 mmol, 20 mol %) was added to this mixture. The solution
was stirred and heated at 60 °C for 24 h. Diethyl ether (10 ml) and water (5 ml)
were then added. The layers were separated and the aqueous phase was
extracted with diethyl ether (3 Â 5 ml). The pooled organic extracts were
washed with 25 ml of water and then with 25 ml of a saturated aqueous
m
(cmÀ1): 3391 [s], 2957–2866 [s], 1649- 1560 [s], 1456–