Donor ligand effects in group 3 metal-catalyzed hydroaminations

Article abstract of DOI:10.1016/j.tetlet.2012.09.019

A series of donor ligands were examined for their effect on group 3 metal-catalyzed intramolecular alkene hydroamination. The cyclization proved to be surprisingly tolerant to the presence of several coordinative functional groups suggesting more latitude

Full text of DOI:10.1016/j.tetlet.2012.09.019

Tetrahedron Letters 53 (2012) 6358–6360
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Donor ligand effects in group 3 metal-catalyzed hydroaminations
⇑
Adrian R. Smith, Helena M. Lovick, Tom Livinghouse
Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 June 2012
Revised 5 September 2012
Accepted 6 September 2012
Available online 14 September 2012
A series of donor ligands were examined for their effect on group 3 metal-catalyzed intramolecular
alkene hydroamination. The cyclization proved to be surprisingly tolerant to the presence of several coor-
dinative functional groups suggesting more latitude with regard to reaction conditions of group 3 metal-
catalyzed processes.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Hydroamination
Group 3 metals
Solvent effects
Catalysis
Stereoselectivity
Due to their unique chemical properties, early transition metal
and lanthanide catalysts possess exceptionally diverse catalytic
applications.1 The range of chemical transformations accessible
to these catalysts spans the activation of inert small molecules2
to olefin polymerization.3 This wide spectrum of reactivity is a con-
sequence of the unusual combination of large ion size, limited
radial extension of valence orbitals, and high coordinative unsatu-
ration of these metals. In this Letter, we present results concerning
the extent to which common donor ligands affect the catalytic
activity of amide complexes derived from these metals.
In order to probe additive effects on catalytic activity, we chose
to apply these catalysts to a classical chemical transformation,
aminoalkene hydroamination/cyclization. Hydroamination has
been the focus of considerable research due to the importance of
the resultant nitrogen-containing products.4 Researchers in our
group, and others, have successfully applied early transition metal
catalysts to this transformation.5
progress was slowed down somewhat in the presence of increasing
quantities of THF, with the reaction time required for >95% conver-
sion being markedly increased (2 weeks) when the cyclization was
performed in neat THF. Although the aforementioned results are
relevant in a preparative sense, we have observed that the overall
rate of product formation is not linear, but decreases with time.9a–g
Accordingly, selected time markers required to achieve ꢀ50% con-
version were obtained for comparative purposes (entries 1 and 7),
with the latter revealing a pronounced deceleration in neat THF.
Other donor ligands were subsequently assayed (Table 2).
Among the neutral ligands, tetrahydrothiophene had no effect (en-
try 1) while 1-methylpyrrolidine slightly slowed the reaction pro-
gress (entry 2). Hydroamination reactions performed in the
Table 1
Additive effects of ethereal ligands
In an initial study, a well-known intramolecular alkene hydro-
amination catalyzed by Y[N(TMS)2]3 was selected.7 We began by
6
examining the reaction progress of yttrium-catalyzed cyclizations
in the presence of common ethereal ligands. Ethereal solvents
are known to coordinate to oxophilic metal complexes and can
suppress catalytic reactivity. In the present context, when used
in small quantities, most ethers had a negligible effect (Table 1,
entries 1–4).8 Even the highly coordinative ether, THF, did not sig-
nificantly impede the reaction progress. To determine if additional
equivalents had a competitive effect, the quantity of THF was
sequentially increased (entries 4–7). As anticipated, the reaction
a
b
Entry
Additive
mol %
t1
t2
1
2
3
4
5
6
7
n/a
0
2.3 h
—
—
—
—
6 h
6 h
6 h
6 h
8 h
9 h
(i-Pr)2O
MTBE
THF
THF
THF
14
14
14
28
56
Neat
—
12 h
THF
336 h (2 weeks)
a
Fifty percentage of conversion, monitored by 1H NMR spectroscopy.
>95% Conversion, monitored by 1H NMR spectroscopy.
⇑
Corresponding author.
E-mail address: livinghouse@chemistry.montana.edu (T. Livinghouse).
b
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.019

A. R. Smith et al. / Tetrahedron Letters 53 (2012) 6358–6360
6359
Table 2
Effect of a series of donor ligands on Y(III)-catalyzed hydroaminations
Table 3
Additive-free hydroamination reactionsa
b
c
M[N(TMS)2]3
2.8 mol %
Entry
1
Additivea
t1
t2
NH2
NH
S
—
—
6 h
C6D6, 25°C
1
2
Me
N
2
3
6.5 h
c
d
Entry
Catalystb
t1
t2
O
Me2N NMe2
O
1
2
3
4
Nd[N(TMS)2]3
Y[N(TMS)2]3
Lu[N(TMS)2]3
0.7 h
2.3 h
30.7 h
90.1 h
4 h
6 h
96 h (4 d)
360 h (15 d)
3.5 d
26 h
19 dd
4 dd,e
e
Sc[N(TMS)2]3
Me2N
Me2N
P
NMe2
4
a
b
c
Reactions were performed in C6D6 at 25 °C.
2.8 mol % of catalyst.
NMe2
P50% Conversion, monitored by 1H NMR spectroscopy.
>95% Conversion by 1H NMR spectroscopy.
5 mol % of catalyst.
5
6
—
—
6.5 h
Me2N
MeO
d
e
7 h (no reactionf)
OMe
O
O
tBuOLi
7
(5.7 hf)
7 h (24 hf)
8
9
10
25.3 h
28.5 h
24.7 h
4 de,g
9 de,g
3 dg
Table 4
tBuONa
Influence of donor ligands on Nd, Lu, and Sc metal precatalysts
Bu4N+ClÀ
b
c
Entry
Metal
Additivea
t1
t2
a
b
c
14 mol %.
P50% Conversion, monitored by 1H NMR spectroscopy.
1
2
3
4
5
6
Nd
Nd
Lu
THF
DME
THF
DME
THF
DME
1.0 h
0.3 h
25.6 h
28.0 h
96.0 h
67.5 h
6.0 h
7.0 h
2.6 d
1.9 d
8.0 d
6.0 d
Reactions were performed in C6D6 at 25 °C using Y[N(TMS)2]3 (2.8 mol %) and
monitored by 1H NMR spectroscopy.
d
2.8 mol % of additive.
Double bond isomerization occurred in the presence of these additives
Lu
Scd
Scd
e
(HMPA—<5%; tBuOLi—15%; tBuONa—21%.
f
Reaction was performed in neat additive at 25 °C.
Reaction was performed at 60 °C with only 2.8 mol % of additive.
a
b
c
g
14 mol % of additive.
P50% Conversion, monitored by 1H NMR spectroscopy.
>95% Conversion by 1H NMR spectroscopy.
5 mol % of catalyst.
d
presence of 14 mol % of hexamethylphosphoramide (HMPA) com-
pletely inhibited hydroamination at 22 °C. However, in the pres-
ence of a lower concentration of HMPA, (e.g., 2.8 mol %), the
reaction proceeded in 4 days at room temperature, with 50% con-
version being realized after 26 h (entry 4).
Neutral, chelating donor ligands were surveyed and revealed
moderate reaction inhibition. Tetramethylethylenediamine (TME-
DA) slightly slowed the hydroamination as did the chelating
ethers, dimethoxyethane (DME) and dioxane (entries 5–7). A com-
parison of the use of THF, DME, and dioxane as solvents provided
an interesting set of results. When the reaction was performed in
THF, hydroamination required two weeks to reach completion (Ta-
ble 1, entry 6). Yet in DME the reaction failed to proceed altogether
(Table 2, entry 6). Out of all the ethers, neat dioxane was the least
inhibitive solvent, requiring only 5.7 h for 50% conversion with
completion observed at 24 h. (Table 2, entry 7).
We subsequently probed the effects of a series of anionic donor
ligands on catalysis (Table 2, entries 8–10). Due to the substantial
rate of suppression resulting from the presence of these charged
additives, hydroaminations were performed at 60 °C, using only
2.8 mol % additive. With lithium tert-butoxide the hydroamination
reaction was completed in four days while the analogous sodium
tert-butoxide reaction required nine days for completion. The coor-
dinative behavior of chloride ions to the lanthanide species is well
known,10 and we found tetrabutylammonium chloride to be sub-
stantially inhibitive (3 days at 60 °C), with the times required for
50% conversion recorded in column 3. It is noteworthy that the
presence of alkoxide additives and HMPA led to considerable
amounts of double bond isomerization of 1 (21% with 2.8 mol %
of tBuONa). However, no alkene isomerization occurred in the
presence of anionic additives or in the absence of the Y(III) catalyst.
The comparatively mild effects of ethereal donor ligands on yt-
trium-catalyzed reactions motivated us to explore the effect of
these additives on other group 3 metals (Nd, Lu, and Sc). The
hydroamination/cyclization of 1 was initially performed in the
presence of several homoleptic bis(trimethylsilyl)amides (Table
3). Of the metal complexes examined, Nd[N(TMS)2]3 and
Y[N(TMS)2]3 most effectively catalyzed the reaction with overall
reaction times of 4 and 6 h, respectively.7 As expected, the reaction
rate decreased as the ionic radius of the metal center decreased.
Accordingly, the scandium tris(amide) was the least efficient cata-
lyst (entry 4). In accord with the proceeding observations, the reac-
tion progress was not linear and slowed considerably subsequent
to 50% conversion.
As noted for the yttrium catalyst, small quantities of ethereal
donor ligands had little influence on the reaction rate when
Nd[N(TMS)2]3 was employed (Table 4). Surprisingly, for the lute-
tium and scandium tris(amide)s, small quantities of 1,2-DME or
THF accelerated hydroamination. This beneficial effect of these li-
gands is possibly due to the inhibition of complex aggregation
and is currently under investigation.
Table 5
Diastereoselectivity effects of ether ligands and alternative solvents
Y[N(TMS)2]3
NH2
NH
5 mol %
90°C
+
cis
3
4
Entry
Additive
Quantity
ta
drb (t/c)
1
2
3
4
5
6
7
Nonec
n/a
6.1 d
5.0 d
8.7 d
9.8 d
4.4 d
3.2 d
2.2 d
6:1
9:1
5:1
6:1
9:1
9:1
8:1
THFc
14 mol %
Neat
Neat
Neat
Neat
Neat
THF
Dioxane
MTBE
C6H5Cl
C6H5(CF3)
a
b
c
>95% Conversion by 1H NMR spectroscopy.
dr = diastereomeric ratio; trans:cis; determined by 1H NMR spectroscopy.
Reaction performed in C6D6.

6360
A. R. Smith et al. / Tetrahedron Letters 53 (2012) 6358–6360
Me
Acknowledgments
Y(L)2
NH
Y[N(TMS)2]3
NH2
alkene
Generous financial support for this research was provided by
the National Institute of General Medical Science and the National
Science Foundation.
- NH(TMS)2
Me
insertion
catalyst activation
Me
NH
Y(L)2
NH
Supplementary data
Me
Me
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
09.019.
protonolysis
Me
NH2
References and notes
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Scheme 1. Simplified mechanism of yttrium-catalyzed intramolecular
hydroamination.
In order to determine the impact of differing concentrations of
THF and the influence of alternative solvents on the stereochemical
aspects of this reaction, we subsequently examined the diastere-
oselectivity of hydroamination/cyclization of 5 in the presence of
precatalyst 4 (Table 5). A small quantity of THF moderately in-
creased trans/cis stereoselectivity with a slight increase in reaction
efficiency (entry 2), while the use of either THF or 1,4-dioxane as
the reaction solvent resulted in a marked suppression of the rate
of hydroamination (entries 3 and 4). In this context it is notewor-
thy that the utilization of t-butyl methyl ether as the reaction sol-
vent resulted not only in an enhancement of rate but also
diastereoselectivity (entry 5). It is also of interest that the substitu-
tion of chlorobenzene or benzotrifluoride for C6D6 resulted in an
appreciable improvement of the efficiency of cyclization and dia-
stereoselectivity (entries 6 and 7).
Potent donor ligands can have a substantial effect on the pro-
gress of early transition metal-catalyzed hydroaminations. Since
Lewis basic compounds are known to coordinate to group 3 metal
complexes, the observed rate suppressions likely arise from addi-
tive-substrate competition during alkene insertion (Scheme 1).11
The concomitant increase in diastereoselectivity is consistent with
donor ligand coordination during the stereochemistry-determining
insertion step, thereby enhancing the steric environment of the
metal center.
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In conclusion, the results presented here suggest considerable
latitude with regard to the reaction conditions available for group
3 metal catalyzed processes. Significantly, in some instances small
amounts of donor ligands (i.e., 1,2-DME, THF) accelerate hydroam-
ination/cyclization (Table 4, Lu and Sc) and can also lead to an in-
crease in diastereoselectivity (Table 5, entry 2). It is also of
considerable interest that the use of alternative solvents (Table 5,
entries 5–7) can result in synthetically beneficial enhancements
in both the reaction rate and stereoselectivity.
11. Motta, A.; Lanza, G.; Fragalà, I. L.; Marks, T. J. Organometallics 2004, 23, 4097–
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