Intramolecular hydroamination/cyclization of aminoalkenes catalyzed by diamidobinaphthyl magnesium- and zinc-complexes

Article abstract of DOI:10.1016/j.tetlet.2009.02.069

Reaction of 2 equiv of n-Bu₂Mg and Et₂Zn with the chiral l-proline-derived axial chiral tetraamines (S,S,S)-1 and (R,S,S)-1 gave the chiral bimetallic complexes [M₂{(S,S,S)-DABN(MeProline)₂}{R}₂] (M=Mg, R=n-Bu ((S,S,S)-2); M=Zn, R=Et ((S,S,S)-3)) and [M₂{(R,S,S)-DABN(MeProline)₂}{R}₂] (M=Mg, R=n-Bu ((R,S,S)-2)); M=Zn, R=Et ((R,S,S)-3)). The magnesium complexes showed moderate to high catalytic activity in the intramolecular hydroamination/cyclization of aminoalkenes, though enantiomeric excess was limited to 14% ee due to protolytic ligand exchange processes. The zinc complexes were less reactive and generally required higher reaction temperatures of 60-100 °C, but achieved slightly higher enantiomeric excess of up to 29% ee.

Full text of DOI:10.1016/j.tetlet.2009.02.069

Tetrahedron Letters 50 (2009) 2054–2056
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular hydroamination/cyclization of aminoalkenes catalyzed
by diamidobinaphthyl magnesium- and zinc-complexes
a
a,b,*
Patricia Horrillo-Martínez , Kai C. Hultzsch
a
Institut für Organische Chemie, Friedrich-Alexander Universität Erlangen-Nürnberg, Henkestr. 42, D-91054 Erlangen, Germany
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Rd., Piscataway, NJ 08854-8087, USA
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of 2 equiv of n-Bu Mg and Et Zn with the chiral
L
-proline-derived axial chiral tetraamines
{(S,S,S)-DABN(MeProline) }{R} ] (M=Mg,
{(R,S,S)-DABN(MeProline) }{R} ] (M=Mg, R=n-Bu
(R,S,S)-2)); M=Zn, R=Et ((R,S,S)-3)). The magnesium complexes showed moderate to high catalytic activ-
2
2
Received 19 December 2008
Accepted 10 February 2009
Available online 14 February 2009
(
S,S,S)-1 and (R,S,S)-1 gave the chiral bimetallic complexes [M
2
2
2
R=n-Bu ((S,S,S)-2); M=Zn, R=Et ((S,S,S)-3)) and [M
2
2
2
(
ity in the intramolecular hydroamination/cyclization of aminoalkenes, though enantiomeric excess was
limited to 14% ee due to protolytic ligand exchange processes. The zinc complexes were less reactive
and generally required higher reaction temperatures of 60–100 °C, but achieved slightly higher enantio-
meric excess of up to 29% ee.
Published by Elsevier Ltd.
The importance of nitrogen-containing compounds, such as
amines, enamines, and imines, as part of natural products and bio-
logical systems has sparked significant research efforts for their
efficient synthesis. Their use is especially important in industrial
basic and fine chemicals, where several million tons of amines
We had previously reported the first chiral lithium-based hydro-
amination catalyst system using -proline-modified diamidobi-
naphthyl ligands. Utilizing these ligands, we report herein the
application of the novel chiral magnesium- and zinc complexes
L
8
[M
2
{(S,S,S)-DABN(MeProline)
2
}{R}
2
]
(M=Mg, R=Bu ((S,S,S)-2);
1
are produced per year. The addition of amines to unsaturated car-
M=Zn, R=Et ((S,S,S)-3)) and [M
2
{(R,S,S)-DABN(MeProline) }{R}
2
2
]
bon–carbon bonds, the so-called hydroamination, generates
amines in a waste-free, highly atom-economical manner, starting
from simple and inexpensive precursors.2 The hydroamination
of alkenes, alkynes, and allenes has been studied using predomi-
(M=Mg, R=n-Bu ((R,S,S)-2); M=Zn, R=Et ((R,S,S)-3)) as catalysts for
the hydroamination/cyclization of non-activated aminoalkenes. To
the best of our knowledge, magnesium has not been investigated
,3
as hydroamination catalyst yet. Also, asymmetric hydroamination
4
5
15,16
nantly catalyst systems based on early and late transition metals.
Alkali metal-based hydroamination catalysts have a long history
going back more than 50 years,6 but recent investigations have
led to improved lithium-based catalysts for the hydroamination
of aminoalkenes is a field of intensive study currently,
date only achiral zinc catalysts have been investigated.
but to
,7
2 2
Addition of 1 equiv of n-Bu Mg or Et Zn to a solution of the L-
proline-derived axial chiral tetraamines (S,S,S)-1 and (R,S,S)-1
8
,9
8
of alkenes. However, the development of a generally applicable
catalyst for the hydroamination of non-activated alkenes remains
a pressing task.
(Scheme 1) in a variety of aliphatic and aromatic solvents gave
only complicated product mixtures. However, addition of 2 equiv
of the dialkylmagnesium reagent or dialkylzinc reagent afforded
well-defined species in both cases (Schemes 1 and 2). According
While base-catalyzed hydroamination has been so far mostly
studied using alkali metal-based catalysts, a few examples of
1
to H NMR spectroscopy, the complexes were formed as bimetallic
10
17
alkaline earth metal-based (calcium and strontium) and zinc-
compounds.
1
1
based catalyst systems have emerged recently. Furthermore,
amido)magnesium (R NMgX, where X = organyl, amide, or alkox-
ide) chemistry is becoming an increasingly active area of study.
In part, this is due to the status gained by lithium amide reagents
(
2
1
2
N
N
Me
1
3
Me
Me
2 n-Bu
2
Mg
N
NH
NH
in synthesis. Being lithium’s diagonal neighbor, magnesium is
clearly of interest since its complexes may offer differing selectiv-
ities and reactivities compared to the lithium derivatives.1
Mg
Mg
C D ,
6
6
N
Me
N
25 ºC, 1h
N
4
(
(
S,S,S)-1
R,S,S)-1
(S,S,S)-2 61%
(R,S,S)-2 76%
*
Corresponding author. Tel.: +1 732 445 1785; fax:+1 732 445 5312.
E-mail address: hultzsch@rci.rutgers.edu (K.C. Hultzsch).
Scheme 1.
0
040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.02.069

P. Horrillo-Martínez, K. C. Hultzsch / Tetrahedron Letters 50 (2009) 2054–2056
2055
Reaction of 2,2-dimethyl-4-pentene-1-amine (4) with 5 mol %
(S,S,S)-2 in C (100 °C, 22 h) produced 5 in 95% yield, but essen-
N
6 6
D
Me
N
tially in racemic form (Table 1, entry 1). In the case of (R,S,S)-2,
10 mol % catalyst was necessary to achieve full conversion of 5,
again, only the racemic product was obtained. The low enantiose-
lectivities for the magnesium catalysts may be explained by a facile
ligand exchange reaction and/or protolytic ligand cleavage upon
addition of the substrate. Facile Schlenk equilibria have impeded
2
equiv Et
2
Zn
Zn
Zn
N
Me
hexanes,
4
8 h, 25 ºC
N
N
N
Me
Me
NH
NH
(S,S,S)-3 67%
N
attempts to perform asymmetric hydroamination using calcium-
Me
N
10b
The observation of a N–H signal in the 1
H
2
equiv Et
2
Zn
based catalysts.
(
S,S,S)-1
Zn
Zn
(
R,S,S)-1
Me
N
NMR spectrum of the reaction mixture indicates the presence of
the protonated form of the ligand. Both magnesium complexes,
(S,S,S)-2 and (R,S,S)-2, showed better catalytic activities at room
6 6
C D ,
3
.5 h, 60 ºC
N
(
R,S,S)-
3
temperature when substrates with sterically more demanding
Scheme 2.
19
gem-dialkyl groups
were used. Cyclization of 2,2-diphenyl-
pent-4-enylamine (6) at room temperature rapidly formed pyrrol-
idine 7 in 6% ee using (S,S,S)-2 and 14% ee using (R,S,S)-2 (Table 1,
entries 5 and 6), while cyclization of C-(1-allyl-cyclohexyl)-
methylamine (8) proceeded significantly slower under the same
conditions (Table 1, entries 5, 6 vs entries 10, 11). Overall, the reac-
tivity of both magnesium catalysts is somewhat lower than that of
Formation of (S,S,S)-2 and (R,S,S)-2 was monitored by NMR
spectroscopy. Completion of ligand complexation was indicated
by the disappearance of the N–H signal at 4.30 ppm ((S,S,S)-1)
and 3.94 ppm ((R,S,S)-1), and by the appearance of a new signal
at 3.59 ppm ((S,S,S)-2) and 3.51 ppm ((R,S,S)-2), respectively, corre-
1
0
calcium and strontium catalysts reported to date. Interestingly,
n-Bu Mg itself did not react with 8 after 2 h at 40 °C. This may indi-
sponding to the methylene group.17 The
a
- and b-methylene
groups of the butyl ligand are diastereotopic, giving two sets of
multiplets each (–0.12 and –0.47 for b-CH
, À1.43 and À1.60 for
–CH ) in the case of (S,S,S)-2. Complexes (S,S,S)-2 and (R,S,S)-2
were isolated as yellow powders in 61% and 76% yield,
2
cate that the protonated diamidobinaphthyl ligand chelates the
catalytically active magnesium species, thus preventing formation
2
2
0
a
2
of unreactive higher aggregates.
The zinc-based complexes (S,S,S)-3 and (R,S,S)-3 are less reac-
tive than the analogous magnesium complexes. Complex (S,S,S)-3
showed higher catalytic activity than (R,S,S)-3, and the reactions
could be performed at lower temperatures (60–80 °C vs 100 °C).
However, (R,S,S)-3 gave the highest enantiomeric excess of 29%
ee for the gem-diphenyl-substituted aminoalkene 6 (Table 1, entry
8), despite the high reaction temperature (100 °C) applied in this
catalytic transformation. As with (S,S,S)-2 and (R,S,S)-2, cyclization
of 8 with the zinc-based catalysts produced essentially racemic
pyrrolidine 9 (Table 1, entries 13 and 14). It is noteworthy that
1
8
respectively.
Reaction of Et
for 48 h led to the zinc complex (S,S,S)-3 as a fine yellow powder in
2
Zn with (S,S,S)-1 in hexanes at room temperature
6
3
7% yield. Complexation of (R,S,S)-1 required heating to 60 °C for
.5 h to form (R,S,S)-3 as a fine yellow powder after drying in va-
cuo; however, the isolated complex was only 86% pure according
1
to H NMR spectroscopy.
With the complexes in hand, we began to investigate their cat-
alytic activity in the hydroamination/cyclization of aminoalkenes.
Table 1
Magnesium- and zinc-catalyzed hydroamination/cyclization of non-activated aminoalkenesa
H
N
R
R
[
cat.]
NH
2
C
6
D
6
R
R
4
6
8
R = Me
R = Ph
5
7
9
R = Me
R = Ph
R-R = -(CH
2
)
5
-
2 5
R-R = -(CH ) -
Entry
Substrate
Catalyst
[cat]/[S] (mol %)
T (°C)
t (h)
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
4
4
4
4
6
6
6
6
8
8
8
8
(S,S,S)-2
(R,S,S)-2
(S,S,S)-3
(R,S,S)-3
(S,S,S)-2
(R,S,S)-2
(S,S,S)-3
(R,S,S)-3
5
10
5
10
4
10
5
10
2
100
100
90
22
21
140
89
0.33
0.17
140
71
2
22
3.5
100
50
20
P99
P99
94
P99
P99
P99
88
P99
0
94
4 (S)
0
2 (S)
3 (R)
6 (R)
14 (R)
13 (S)
29 (R)
n/a
0
6 (R)
n/a
100d
22
e
e
22
60
100
40
22
22
60
80
100
2
n-Bu Mg
(S,S,S)-2
(R,S,S)-2
1
1
1
1
1
5
e
10
10
5
80
P99
97
2
Et Zn
f
8
8
(S,S,S)-3
(R,S,S)-3
5 (S)
0
10
P99
a
Reaction conditions: 0.2 mmol substrate, 0.5 mL C
6
D
6
, Ar atm.
b
c
d
e
f
Determined by 1H NMR spectroscopy.
19
Determined by F NMR spectroscopy of the Mosher amides at 60 °C.
8
Reaction in toluene-d .
0
0
.1 mmol substrate.
.4 mmol substrate. n/a = not applicable.

2
056
P. Horrillo-Martínez, K. C. Hultzsch / Tetrahedron Letters 50 (2009) 2054–2056
Eichberger, M.; Hartung, C. G.; Seayad, J.; Thiel, O. R.; Tillack, A.; Trauthwein, H.
Et
2
Zn, which had been previously shown to mediate hydroamina-
11c
Synlett 2002, 1579–1594.
(a) Closson, R. D.; Napolitano, J. P.; Ecke, G. G.; Kolka, A. J. Org. Chem. 1957, 22,
tion/cyclization of aminoalkynes,
of 8 at 60 °C to give the desired pyrrolidine in quantitative conver-
sion within 4 days.
catalyzes also the cyclization
6.
646–649; (b) Howk, B. W.; Little, E. L.; Scott, S. L.; Whitman, G. M. J. Am. Chem.
Soc. 1954, 76, 1899–1902; (c) Wegler, R.; Pieper, G. Chem. Ber. 1950, 83, 1–6.
Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. Adv. Synth. Catal. 2002, 344, 795–
7.
8.
9.
The present study was aimed to ascertain the catalytic activity
of magnesium-based hydroamination catalysts. While (S,S,S)-2
and (R,S,S)-2 displayed only poor enantioselectivities in asymmet-
ric hydroaminations, they certainly show that magnesium-based
catalysts are viable, and that the chelating nature of the diamido-
binaphthyl ligands can enhance catalytic activity by prevention
of aggregate formation. The catalytic activity of the magnesium
complexes seems to be of similar order of magnitude, though
somewhat reduced, in comparison to calcium- and strontium-
based catalysts. Facile ligand redistribution processes leading to
achiral catalytic active species have thwarted our efforts to achieve
appreciable enantioselectivities with these catalysts. The zinc-
based catalysts show for the first time the feasibility of asymmetric
hydroamination even under the harsh reaction conditions required
for these catalysts, although the observed enantioselectivities are
low. In order to improve catalyst efficiency and selectivity, we be-
lieve that it is imperative to utilize chiral ligands that will mini-
813.
Horrillo Martínez, P.; Hultzsch, K. C.; Hampel, F. Chem. Commun. 2006, 2221–
2223.
(a) Quinet, C.; Jourdain, P.; Hermans, C.; Ates, A.; Lucas, I.; Marko, I. E.
Tetrahedron 2008, 64, 1077–1087; (b) Ogata, T.; Ujihara, A.; Tsuchida, S.;
Shimizu, T.; Kaneshige, A.; Tomioka, K. Tetrahedron Lett. 2007, 48, 6648–6650;
(c) Horrillo-Martínez, P.; Hultzsch, K. C.; Gil, A.; Branchadell, V. Eur. J. Org. Chem.
2
007, 3311–3325; (d) Ates, A.; Quinet, C. Eur. J. Org. Chem. 2003, 1623–1626.
0. (a) Datta, S.; Gamer, M. T.; Roesky, P. W. Organometallics 2008, 27, 1207–1213;
b) Buch, F.; Harder, S. Z. Naturforsch. 2008, 63b, 169–177; (c) Datta, S.; Roesky,
1
(
P. W.; Blechert, S. Organometallics 2007, 26, 4392–4394; (d) Crimmin, M. R.;
Casely, I. J.; Hill, M. S. J. Am. Chem. Soc. 2005, 127, 2042–2043.
1
0
1
1. (a) Dochnahl, M.; Löhnwitz, K.; Pissarek, J.-W.; Roesky, P. W.; Blechert, S. Dalton
Trans. 2008, 2844–2848; (b) Dochnahl, M.; Löhnwitz, K.; Pissarek, J.-W.;
Biyikal, M.; Schulz, R.; Schön, S.; Meyer, N.; Roesky, P. W.; Blechert, S. Chem.
Eur. J. 2007, 13, 6654–6666; (c) Yin, Y.; Ma, W.; Chai, Z.; Zhao, G. J. Org. Chem.
2007, 72, 5731–5736; (d) Meyer, N.; Löhnwitz, K.; Zulys, A.; Roesky, P. W.;
Dochnahl, M.; Blechert, S. Organometallics 2006, 25, 3779–3783; (e) Dochnahl,
M.; Pissarek, J.-W.; Blechert, S.; Löhnwitz, K.; Roesky, P. W. Chem. Commun.
2006, 3405–3407; (f) Zulys, A.; Dochnahl, M.; Hollmann, D.; Löhnwitz, K.;
Herrmann, J.-S.; Roesky, P. W.; Blechert, S. Angew. Chem. Int. Ed. 2005, 44,
7
2
794–7798; (g) Shanbhag, G. V.; Halligudi, S. B. J. Mol. Catal. A: Chem. 2004, 222,
23–228; (h) Bódis, J.; Müller, T. E.; Lercher, J. A. Green Chem. 2003, 5, 227–231;
mize ligand
redistribution
processes
and
provide
a
configurational stable coordination environment around the metal
center under conditions of catalytic hydroamination.
(i) Neff, V.; Müller, T. E.; Lercher, J. A. Chem. Commun. 2002, 906–907; (j)
Müller, T. E.; Grosche, M.; Herdtweck, E.; Pleier, A.-K.; Walter, E.; Yan, Y.-K.
Organometallics 2000, 19, 170–183; (k) Müller, T. E.; Pleier, A.-K. J. Chem. Soc.
Dalton Trans. 1999, 583–588.
Acknowledgments
12. (a) Bonafoux, D.; Bordeau, M.; Biran, C.; Cazeau, P.; Dunogues, J. J. Org. Chem.
996, 61, 5532–5536; (b) Kondo, Y.; Yoshida, A.; Sakamoto, T. J. Chem. Soc.,
1
Perkin Trans. 1 1996, 2331–2332; (c) Van Draanen, N. A.; Arseniyadis, S.;
Crimmins, M. T.; Heathcock, C. H. J. Org. Chem. 1991, 56, 2499–2506; (d) Eaton,
P. E.; Lee, C.-H.; Xiong, Y. J. Am. Chem. Soc. 1989, 111, 8016–8018.
3. For reviews of lithium amides as reagents in organic synthesis, see: (a) Cox, P.
J.; Simpkins, N. S. Tetrahedron: Asymmetry 1991, 2, 1–26; (b) Snieckus, V. Chem.
Rev. 1990, 90, 879–933.
4. For reviews of magnesium amides and their application in organic synthesis,
see: (a) Shimizu, M.. In Science of Synthesis: Compounds of Groups 13 and 2 (Al,
Ga, In, Tl, Be ... Ba); Noyori, R., Ed.; Georg Thieme Verlag KG: Stuttgart, 2004;
Vol. 7, pp 661–668; (b) Henderson, K. W.; Kerr, W. J. Chem. Eur. J. 2001, 7, 3430–
Generous financial support by the Deutsche Forschungsgemeins-
chaft (DFG Emmy Noether programme) is gratefully acknowledged.
1
1
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.069.
3437.
1
5. For reviews on asymmetric hydroamination see: (a) Aillaud, I.; Collin, J.;
Hannedouche, J.; Schulz, E. Dalton Trans. 2007, 5105–5118; (b) Hultzsch, K. C.
Adv. Synth. Catal. 2005, 347, 367–391; (c) Hultzsch, K. C. Org. Biomol. Chem.
References and notes
1
.
.
(a) Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008–2022; (b) Takabe, K.;
Katagiri, T.; Tanaka, J. Bull. Chem. Soc. Jpn. 1973, 46, 222–225.
For comprehensive and general hydroamination reviews, see: (a) Müller, T. E.;
Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795–3892;
2005, 3, 1819–1824; (d) Roesky, P. W.; Müller, T. E. Angew. Chem. Int. Ed. 2003,
4
2, 2708–2710.
2
1
6. For selected, leading examples for asymmetric hydroamination see: (a) Zhou,
J.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 12220–12221; (b) Aillaud, I.; Collin,
J.; Duhayon, C.; Guillot, R.; Lyubov, D.; Schulz, E.; Trifonov, A. Chem. Eur. J. 2008,
(
b) Brunet, J. J.; Neibecker, D. In Catalytic Heterofunctionalization from
Hydroamination to Hydrozirconation; Togni, A., Grützmacher, H., Eds.; Wiley-
VCH: Weinheim, 2001; pp 91–141; (c) Müller, T. E.; Beller, M. Chem. Rev. 1998,
1
4, 2189–2200; (c) LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am.
Chem. Soc. 2007, 129, 2452–2453; (d) Zhang, Z.; Bender, C. F.; Widenhoefer, R.
A. J. Am. Chem. Soc. 2007, 129, 14148–14149; (e) Wood, M. C.; Leitch, D. C.;
Yeung, C. S.; Kozak, J. A.; Schafer, L. L. Angew. Chem. Int. Ed. 2007, 46, 354–358;
98, 675–703.
3
.
.
(a) Taube, R. In Applied Homogeneous Catalysis; Cornils, B., Herrmann, W. A.,
Eds.; Wiley-VCH: Weinheim, 1996; Vol. 1, pp 507–520; (b) Steinborn, D.;
Taube, R. Z. Chem. 1986, 26, 349–359.
For reviews on early transition metal catalyzed hydroaminations, see: (a)
Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36, 1407–1420; (b) Lee, A. V.; Schafer,
L. L. Eur. J. Inorg. Chem. 2007, 2245–2255; (c) Odom, A. L. Dalton Trans. 2005,
(
f) Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748–
3
4
759; (g) Watson, D. A.; Chiu, M.; Bergman, R. G. Organometallics 2006, 25,
731–4733; (h) Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 1737–1739.
4
1
1
7. See Supplementary data.
8. The isolated magnesium complexes (S,S,S)-2 and (R,S,S)-2 retained heptane
2
25–233; (d) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673–686; (e) Doye,
S. Synlett 2004, 1653–1672; (f) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003,
35–946; (g) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104–114.
(a) Brunet, J.-J.; Chu, N.-C.; Rodriguez-Zubiri, M. Eur. J. Inorg. Chem. 2007, 4711–
722; (b) Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006, 4555–4563; (c)
Hartwig, J. F. Pure Appl. Chem. 2004, 76, 507–516; (d) Beller, M.; Breindl, C.;
from the dibutylmagnesium solution according to their 1H NMR spectra.
Attempts to remove this residual heptane have been unsuccessful so far, due to
the high sensitivity of the compounds.
9
5
.
1
2
9. Jung, M. E.; Pizzi, G. Chem. Rev. 2005, 105, 1735–1766.
0. Clegg, W.; Craig, F. J.; Henderson, K. W.; Kennedy, A. R.; Mulvey, R. E.; O’Neil, P.
A.; Reed, D. Inorg. Chem. 1997, 36, 6238–6246.
4