C2-symmetric zirconium Bis(Amidate) complexes with enhanced reactivity in aminoalkene hydroamination

Article abstract of DOI:10.1021/om9008907

Binaphthalenedicarboxamide zirconium complexes exhibit significantly enhanced catalytic activity in aminoalkene hydroamination reactions with respect to substrate scope (substrates without gem-dialkyl activation; cyclization of aminoheptenes), catalyst loading (as low as 0.5 mol %) and reaction temperatures (as low as 70 °C) compared to previous group 4 metal-based hydroamination catalyst systems.

Full text of DOI:10.1021/om9008907

24 Organometallics 2010, 29, 24–27
DOI: 10.1021/om9008907
C2-Symmetric Zirconium Bis(Amidate) Complexes with Enhanced
Reactivity in Aminoalkene Hydroamination
Alexander L. Reznichenko and Kai C. Hultzsch*
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey,
610 Taylor Road, Piscataway, New Jersey 08854-8087
Received October 12, 2009
Summary: Binaphthalenedicarboxamide zirconium complexes
Group 4 metal-based catalyst systems have been studied
intensively in the hydroamination of alkynes and allenes,2i-o,6
exhibit significantly enhanced catalytic activity in aminoalk-
ene hydroamination reactions with respect to substrate scope
(substrates without gem-dialkyl activation; cyclization of
aminoheptenes), catalyst loading (as low as 0.5 mol %) and
reaction temperatures (as low as 70 °C) compared to previous
group 4 metal-based hydroamination catalyst systems.
(4) For asymmetric hydroamination reactions of aminoalkenes with
group 4 metal catalysts, see: (a) Knight, P. D.; Munslow, I.; O’Shaugh-
nessy, P. N.; Scott, P. Chem. Commun. 2004, 894. (b) Watson, D. A.; Chiu,
M.; Bergman, R. G. Organometallics 2006, 25, 4731. (c) Wood, M. C.;
Leitch, D. C.; Yeung, C. S.; Kozak, J. A.; Schafer, L. L. Angew. Chem., Int.
Ed. 2007, 46, 354. (d) Gott, A. L.; Clarke, A. J.; Clarkson, G. J.; Scott, P.
Organometallics 2007, 26, 1729. (e) Gott, A. L.; Clarkson, G. J.; Deeth, R. J.;
Hammond, M. L.; Morton, C.; Scott, P. Dalton Trans. 2008, 2983. (f) Gott,
A. L.; Clarke, A. J.; Clarkson, G. J.; Scott, P. Chem. Commun. 2008, 1422.
(g) Xiang, L.; Song, H.; Zi, G. Eur. J. Inorg. Chem. 2008, 1135. (h) Zi, G.;
Wang, Q.; Xiang, L.; Song, H. Dalton Trans. 2008, 5930. (i) Zi, G.; Liu, X.;
Xiang, L.; Song, H. Organometallics 2009, 28, 1127.
The importance of nitrogen containing compounds in
biological systems and industrially relevant basic and
fine chemicals has sparked significant research efforts to
develop efficient synthetic protocols.1 One of the simplest
approaches, the hydroamination, has found significant
attention only in recent years with the development of more
efficient transition metal-based catalyst systems.2 The
addition of amine N-H functionalities to unsaturated
carbon-carbon bonds generates amines in a waste-free,
highly atom-economical manner starting from simple and
inexpensive precursors. An area of particular interest has
been the generation of new stereogenic center during the
hydroamination process, but the development of chiral
catalysts for the asymmetric hydroamination of alkenes
(AHA) has remained challenging.3-5
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Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748. (l) Horrillo Martínez, P.;
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(n) Ogata, T.; Ujihara, A.; Tsuchida, S.; Shimizu, T.; Kaneshige, A.; Tomioka,
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Walsh, P. J.; Bergman, R. G. J. Am. Chem. Soc. 1993, 115, 2753. (c) Haak,
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(k) Khedkar, V.; Tillack, A.; Beller, M. Org. Lett. 2003, 5, 4767. (l) Li, C.;
Thomson, R. K.; Gillon, B.; Patrick, B. O.; Schafer, L. L. Chem. Commun.
2003, 2462. (m) Ackermann, L. Organometallics 2003, 22, 4367.
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*To whom correspondence should be addressed. E-mail: hultzsch@
rci.rutgers.edu.
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pubs.acs.org/Organometallics
Published on Web 12/08/2009
2009 American Chemical Society

Communication
Organometallics, Vol. 29, No. 1, 2010 25
while reactions involving unactivated alkenes have emerged
only in recent years.7 Schafer4c,6j,l,q,r,7d,g,8 has developed
amidate titanium and zirconium hydroamination catalysts
that exhibit promising hydroamination activity, including
cyclization of primary aminoalkenes. Chiral variants of these
catalysts developed in Schafer’s4c and Scott’s4d group have
displayed enantioselectivities of up to 93% ee.
Scheme 1. Preparation of Binaphthalenedicarboxamide Ligands
and Their Corresponding Zirconium Complexes
Alkene hydroamination with group 4 metal-based catalysts
requires significant harsher reaction conditions (>100 °C)
and higher catalyst loadings (typically 5-10 mol %) in
comparison to rare earth metal-based catalysts.2h,5a,k,9 With
a few exceptions,4b,7c,k neutral group 4 metal catalyst systems
have been limited to gem-dialkyl-activated aminoalkenes.
Cyclization of aminoheptenes led to the unexpected forma-
tion of the hydroaminoalkylation product rather than the
anticipated 7-membered ring hydroamination product.10-12
However, easier catalyst preparation and handling, as well as
potential higher functional group tolerance, may compen-
sate for this disadvantage.
We selected binaphthalenedicarboxylic acid (BINCA) as a
key starting material for the preparation of novel bis-
(amidate) ligands, based on its readily availability and
excellent configurational stability.13 To our surprise, no
bis(amidate) BINCA-based ligands have been reported so
far.14 For our initial study we selected a few aromatic amines
with varying steric demand to synthesize corresponding
zirconium bis(amidate) complexes.
1b-c with Zr(NMe2)4 led to well-defined C2-symmetric spe-
cies 2 (Scheme 1), which can be formulated as the amine
adduct (1)Zr(NMe2)2(NHMe)2.15
The observation of a single carbonyl signal for 2b,c in
the 13C NMR spectrum at around 161 ppm is indicative of a
κ1-binding mode of the amidate ligand.4d The reaction of the
least sterically demanding ligand 1a led an unsymmetric
species with two carbonyl signals at 160.8 and 178.6 ppm,
which is indicative of different binding modes (κ1/κ2) of the
two amidate moieties. The precatalysts 2a,b may be isolated
by removal of the solvent in vacuo with retention of two
equivalents of dimethylamine. However, removal of solvent
from the sterically most hindered complex 2c produced the
mono(amine) adduct (1c) Zr(NMe2)2(HNMe2) (2c0) with
two κ1 bound amidate moieties.15 The catalysts exhibited
the same reactivity independently of being isolated or gen-
erated in situ. Thus, for convenience the catalysts were
generally prepared in situ and used as a standard solution.
A screening of complexes 2a-c in various catalytic hydro-
amination/cyclization reactions revealed a remarkable increase
in catalytic performance compared to previously studied
group 4 alkene hydroamination catalyst systems. Most
notably, reactions could be performed with catalyst loadings
as low as 0.5 mol % (Table 1, entry 13) and reaction
temperatures as low as 70 °C (Table 1, entry 5).
The synthesis of the desired bis(amide) proligands pro-
ceeded in a convenient two-step, one-pot sequence (Scheme 1)
in moderate yields. Subsequent reaction of the proligands
(7) For hydroamination reactions of aminoalkenes with achiral
group 4 metal catalysts, see: (a) Gribkov, D. V.; Hultzsch, K. C. Angew.
Chem., Int. Ed. 2004, 43, 5542. (b) Bexrud, J. A.; Beard, J. D.; Leitch, D. C.;
Schafer, L. L. Org. Lett. 2005, 7, 1959. (c) Kim, H.; Lee, P. H.; Livinghouse,
T. Chem. Commun. 2005, 5205. (d) Thomson, R. K.; Bexrud, J. A.; Schafer,
L. L. Organometallics 2006, 25, 4069. (e) M€uller, C.; Loos, C.; Schulenberg,
N.; Doye, S. Eur. J. Org. Chem. 2006, 2499. (f) Kim, H.; Kim, Y. K.; Shim,
J. H.; Kim, M.; Han, M.; Livinghouse, T.; Lee, P. H. Adv. Synth. Catal. 2006,
348, 2609. (g) Bexrud, J. A.; Li, C.; Schafer, L. L. Organometallics 2007, 26,
6366. (h) Stubbert, B. D.; Marks, T. J. J. Am. Chem. Soc. 2007, 129, 6149.
ꢀ
(i) Marcsekova, K.; Loos, C.; Rominger, F.; Doye, S. Synlett 2007, 2564.
(j) Ackermann, L.; Kaspar, L. T.; Althammer, A. Org. Biomol. Chem. 2007,
5, 1975. (k) Majumder, S.; Odom, A. L. Organometallics 2008, 27, 1174.
€
(l) M€uller, C.; Saak, W.; Doye, S. Eur. J. Org. Chem. 2008, 2731. (m) Grabe,
K.; Pohlki, F.; Doye, S. Eur. J. Org. Chem. 2008, 4815. (n) M€uller, C.; Koch,
R.; Doye, S. Chem.;Eur. J. 2008, 14, 10430. (o) Bexrud, J. A.; Schafer,
L. L. Dalton Trans. [Online early access]. DOI: 10.1039/b913393c. (p) Manna,
K.; Ellern, A.; Sadow A. D. Chem. Commun. [Online early access]. DOI:
10.1039/b918989k.
As anticipated, increasing steric bulk of the gem-dialkyl-
substituent in aminopentenes 3a-d resulted in higher rates of
cyclization, allowing it to perform cyclizations with low
catalyst loadings and lower reaction temperatures. In the
absence of any gem-dialkyl-substituent the cyclization of 3e
required slightly higher reaction temperatures, higher cata-
lyst loadings, and longer reaction times (Table 1, entries 16
and 17). However, there are only a limited set of group 4
metal catalysts capable to cyclize this substrate and they
(8) Lee, A. V.; Schafer, L. L. Eur. J. Inorg. Chem. 2007, 2245.
ꢀ
(9) Gagne, M. R.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1992,
114, 275.
(10) For a brief review on hydroaminoalkylation, see: Roesky, P. W.
Angew. Chem., Int. Ed. 2009, 48, 4892.
(11) (a) Bexrud, J. A.; Eisenberger, P.; Leitch, D. C.; Payne, P. R.;
Schafer, L. L. J. Am. Chem. Soc. 2009, 131, 2116. (b) Kubiak, R.;
Prochnow, I.; Doye, S. Angew. Chem., Int. Ed. 2009, 48, 1153. (c)
Prochnow, I.; Kubiak, R.; Frey, O. N.; Beckhaus, R.; Doye, S. ChemCatCh-
em 2009, 1, 162.
(12) Tantalum catalyzed hydroaminoalkylation: (a) Clerici, M. G.;
Maspero, F. Synthesis 1980, 305. (b) Nugent, W. A.; Ovenall, D. W.;
Holmes, S. J. Organometallics 1983, 2, 161. (c) Herzon, S. B.; Hartwig, J. F.
J. Am. Chem. Soc. 2007, 129, 6690. (d) Herzon, S. B.; Hartwig, J. F. J. Am.
Chem. Soc. 2008, 130, 14940. (e) Eisenberger, P.; Ayinla, R. O.; Lauzon,
J. M. P.; Schafer, L. L. Angew. Chem., Int. Ed. 2009, 48, 8361. (f) As a side
reaction in alkali metal-catalyzed hydroamination reactions: Horrillo-Martí-
nez, P.; Hultzsch, K. C.; Hampel, F. Eur. J. Org. Chem. 2007, 3311.
(13) Oi, S.; Matsuzaka, Y.; Yamashita, J.; Miyano, S. Bull. Chem.
Soc. Jpn. 1989, 62, 956.
(15) The complexes were isolated as mono(amine) adduct (complex
2c0, see Supporting Information) and bis(amine) adducts (complexes 2a
and 2b) based on NMR spectroscopy. The reaction of the proligands 1
with Ti(NMe2)4 lead to a mixture of products and we are currently
attempting to identify and separate these species.
(16) The only previous example of hydroamination/cyclization of an
aminoheptene with a group 4 metal catalyst has been reported recently
by Schafer while studying the hydroaminoalkylation reaction. The
achiral bis(amidate) zirconium catalyst required forcing reaction condi-
tions (20 mol % cat., 145 °C, 115 h, 55% conv), see ref 11a and 7o.
(14) Schafer and co-workers have reported recently related biphenyl-
based bis(amidate) tantalum catalysts for hydroaminoalkylation,
see ref 12e.

26 Organometallics, Vol. 29, No. 1, 2010
Reznichenko and Hultzsch
Table 1. Zirconium-Catalyzed Asymmetric Hydroamination of
Aminoalkenesa
Table 2. Diastereoselective Hydroamination/Cyclization of
r-Substituted Aminopentenes
subst
cat
t, h
trans/cis
yield, %a
9a
9b
9c
2b
2b
2a
20
25
12
15:1
>30:1
>30:1
94
95
88b
a NMR yield based on 1H NMR spectroscopy using ferrocene as
internal standard. b Isolated yield.
entry
subst
cat (mol %)
conditionsb
% ee (config)
κ1 binding mode of the amidate moieties leading to a more
electron deficient, thus more reactive metal center. On the
other hand, this κ1 binding mode puts the stereodirecting
N-aryl substituents in a more remote position, pointing away
from the metal center.17 Therefore, it is not too astonishing
that the enantioselectivities achieved with complexes 2
do not compare well with the highest selectivities achieved
to date in group 4 metal catalyzed alkene hydroamination
reactions.4a-d Nevertheless, it seems remarkable that
the highest selectivity of 60% ee was observed in the forma-
tion of the azepane 8 using catalyst 2a. Generally, the
sterically less demanding mesityl substituent in 2a resulted
in higher enantioselectivities, which may be rationalized by a
mixed κ1/κ2-binding mode of the two amidate moieties in this
complex.
The scope of the reaction is not limited to terminal olefins,
but also the internal olefin 3f was cyclized efficiently. Cycli-
zation of R-alkyl substituted aminopentenes proceeded with
high trans/cis diastereoselectivities (Table 2), but no kinetic
resolution of the starting material was observed.5k,18,19
Cyclization of 11 (eq 1) proceeded chemoselectively with-
out any substrate isomerization, remarkably contrasting our
observations with binaphtholate rare earth metal com-
plexes19 that are highly resistant to olefin isomerizations
otherwise.
1
2
3
4
5
6
7
8
3a
3a
3a
3b
3b
3b
3b
3b
3c
3c
3c
3c
3c
3d
3d
3e
3e
3f
(S)-2a (2)
(R)-2b (2)
(S)-2c (5)
(S)-2a (2)
(S)-2a (6)
(R)-2b (2.5)
(R)-2b (1)
(S)-2c (2)
(S)-2a (2)
(S)-2a (2)
(R)-2b (1)
(S)-2c (2)
(rac)-2c (0.5)
(S)-2a (2)
(R)-2b (2)
(S)-2a (8)
(R)-2b (3)
(S)-2a (6)
(S)-2a (4)
(R)-2b (2)
(S)-2a (2)
(S)-2a (8)
(R)-2b (10)
100 °C, 26 h
100 °C, 7 h
110 °C, 6 h
100 °C, 12 h
70 °C, 28 h
90 °C, 7 h
90 °C, 12 h
110 °C, 3 h
100 °C, 3 h
80 °C, 14 h
100 °C, 2.5 h
100 °C, 1.5 h
100 °C, 6 h
90 °C, 13 h
90 °C, 9 h
120 °C, 39 h
110 °C, 72 h
110 °C, 16 h
100 °C, 3 h
100 °C, 3 h
100 °C, 7 h
120 °C, 51 h
120 °C, 72 h
23 (R)
42 (S)c
<5% (R)
14 (R)
16 (R)
27 (S)
26 (S)
11 (S)
54 (S)
52 (S)d
36 (R)
39 (S)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
60/0e
48/48f
7 (R)
6 (S)
8
5a
5a
5b
7
33
26
7
60g
53
7
a Reaction conditions: C6D6, Ar atm. b Greater than 95% conv based
on 1H NMR spectroscopy using ferrocene as internal standard. c Iso-
lated yield is 84%. d Isolated yield is 85%. e dr = 1.6:1. f dr = 1.8:1.
g NMR yield is 94%.
typically require harsher reaction conditions (g10 mol %
catalyst loading, g120 °C).4b,7c,k Complexes 2 catalyze not
only the cyclization of aminohexenes 5a,b, they also facilitate
formation of the azepane 8 (Table 1, entries 22 and 23),16
which is the first example for an enantioselective 7-mem-
bered ring formation via catalytic hydroamination. This
contrasts previous reported attempts of hydroamination/
cyclization of aminoheptene derivatives that either gave no
product7b,e,l or resulted in a hydroaminoalkylation process
instead.10-12 In fact, under the catalytic conditions em-
ployed in this study, we did not observe hydroaminoalkyla-
tion or olefin isomerization4a,7a,b,11b products in any of the
catalytic reactions.
However, no reaction was observed for the N-benzyl
aminopentene derivative 13 even under more forcing
reaction conditions (eq 2), which is in agreement to
(18) The starting material remained racemic at conversions as high as
86%. It is conceivable that the zirconium catalysts may racemize the
substrate, see: Pohlki, F.; Bytschkov, I.; Siebeneicher, H.; Heutling, A.;
Although still speculative at this point, the significant
higher reactivity of complexes 2 in comparison to previously
studied group 4 metal alkene hydroamination catalysts
(including amidate complexes) may be attributed to the
€
Konig, W. A.; Doye, S. Eur. J. Org. Chem. 2004, 1967. However,
cyclization of enantiomerically pure 9a did not show any sign of racemization
of the starting material.
(19) Reznichenko, A. L.; Hampel, F.; Hultzsch, K. C. Chem.;Eur. J.
2009, 15, 12819.
(17) As observed by Schafer in the crystal structure of a biphenyl-
based bis(k1-amidate) tantalum complex, see ref 12e. Coincidentally, the
highest enantioselectivity achieved with this catalyst system in the
hydroaminoalkylation of norbornene was 61% ee.
(20) A few neutral group 4 metal catalyst systems have been reported
to catalyze the hydroamination/cyclization of secondary aminoalkenes,
which has been interpreted in terms of an alternative lanthanide-like
σ-bond metathesis mechanism, see refs 7h, 7k, and 7l.

Communication
Organometallics, Vol. 29, No. 1, 2010 27
most20 previous studies on neutral group 4 metal based
catalysts.4c,7b,d
rate of cyclization, which is highly indicative (in conjunction
with the first order rate dependence on catalyst con-
centration) that the resting state of the catalyst in this process
is a monometallic species. A strong primary kinetic isotope
effect of 4.2 in the cyclization of 3b is in agreement to a
previous study by Scott4f and the resulting pyrrolidine 4b-d2
shows deuteration exclusively at the R-methyl position
(as well as at nitrogen).
We are currently performing further catalytic and mechan-
istic studies toward the scope and limitation of complexes 2
in order to improve enantioselectivity and improve our
understanding of the increased reactivity of these new cata-
lysts.
This finding has been interpreted as an indicator for a [2 þ
2]-cycloaddition mechanism analogous to group 4 metal-
catalyzed alkyne and allene hydroaminations,6a,b,d,21 as the
secondary amine does not allow formation of a metal imido
species required in this mechanism.20
Some initial kinetic studies22 indicate that the reaction is
first order in aminoalkene substrate and catalyst, which is in
agreement to some studies,7d,l while others have observed a
zero order rate dependence on substrate concentration.4f,7h
Certainly, the reaction order in substrate depends on the
underlying reaction mechanism and the structure of the
catalytic active species. To that end, it is interesting to note
that enantiopure and racemic catalysts 2 exhibited the same
Acknowledgment. We would like to thank Professor
Laurel Schafer for sharing unpublished information. We
are indebted to Professor Daniel Seidel and Eric Klauber
for their kind assistance with obtaining HPLC data.
Supporting Information Available: Experimental procedures
and characterization data, NMR spectra of ligands 1a-c,
complexes 2a-c, catalytic reactions and Mosher amides, kinetic
experiments. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) (a) Pohlki, F.; Doye, S. Angew. Chem., Int. Ed. 2001, 40, 2305.
(b) Straub, B. F.; Bergman, R. G. Angew. Chem., Int. Ed. 2001, 40, 4632.
(22) See Supporting Information for details.