Chiral neutral zirconium amidate complexes for the asymmetric hydroamination of alkenes

Article abstract of DOI:10.1002/anie.200603017

Aminations with amidates: The first C₂-symmetric amidate complexes of zirconium were used for catalytic asymmetric hydroaminations of amino alkenes to prepare chiral gem-disubstituted pyrrolidines with up to 93 % ee (see scheme). The modular nature of the chiral complexes facilitates their preparation and screening as catalysts. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200603017

Communications
DOI: 10.1002/anie.200603017
Asymmetric Catalysis
Chiral Neutral Zirconium Amidate Complexes for the
Asymmetric Hydroamination of Alkenes**
Mark C. Wood, David C. Leitch, Charles S. Yeung, Jennifer A. Kozak, and
Laurel L. Schafer*
Angewandte
Chemie
354
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À
The formation of C N bonds in an enantioselective fashion is
a significant challenge in the synthesis of pharmaceuticals and
Herein, we disclose the first chiral neutral amidate zirconium
complexes that can be used for enantioselective cyclohydro-
amination of primary aminoalkenes with up to 93% ee, which
is, to the best of our knowledge, the highest reported
enantioselectivity for this typical test substrate.[3]
The auxiliary amide proligands used for our systems were
easily prepared from amines and acid chlorides, resulting in
proligands with varying steric and electronic properties.[8a,b] In
an effort to control both coordination isomerism and chirality
at the metal center, the known rigid and axially chiral 2,2’-
diamino-6,6’-dimethylbiphenyl backbone[11] was used in com-
bination with three different sterically demanding acid
chloride reagents to prepare tethered bis(amide) proligands
3a–c (see Scheme 1). It is known that amidate ligands can
fine chemicals. The generation of a stereogenic center by the
À
=
selective addition of N H to C C bonds is efficiently
accomplished by catalytic asymmetric hydroamination,
which is a stereoselective, atom-economic transformation
for the generation of enantioenriched a-chiral amines.[1]
Despite intense investigation, to date, there are no general
catalysts for this demanding synthetic transformation.[2] Most
breakthroughs in this area have been accomplished using
rare-earth-metal catalysts.[3] However, Group 4 metal cata-
lysts are particularly attractive owing to their low cost, low
toxicity, high reactivity, and established utility in asymmetric
catalysis.[4] An important advancement in enantioselective
hydroaminations catalyzed by Group 4 metals was a cationic
zirconium complex developed by Scott and co-workers[5] for
the asymmetric hydroamination of select secondary amino-
alkenes.[5,6] Also, some chiral late-transition-metal complexes
have been investigated for enantioselective intermolecular
hydroamination, with good results obtained for activated
alkene and alkyne substrates.[7] Certainly, the development of
easily prepared catalysts for general use in the enantioselec-
tive hydroamination of a broad range of alkenes remains a
critical goal.
As an entry into developing new catalysts for this
challenging reaction, our group has been investigating a
family of modular titanium and zirconium bis(amidate)
precatalysts for the catalytic hydroamination of alkynes,[8]
allenes,[9] and alkenes.[10] Recently, we showed that the Zr
and Ti bis(amidate) complexes 1 and 2 can be used for the
preparation of 2,4,4-trimethylpyrrolidine as a racemate, with
Zr complex 1 being the most active catalyst [Eq. (1)].[10]
Scheme 1. Facile preparation of chiral Zr bis(amidate)complexes.
adopt multiple bonding motifs,[12] and, importantly, Arnold
and co-workers previously reported the application of a
tethered amide proligand for the preparation of bimetallic
titanium complexes.[13] However, in our case, the orientation
of the amine groups in the selected chiral backbone in
combination with the steric bulk imposed by the carbonyl
substituents was anticipated to both favor the formation of
monomeric complexes and impose a well-defined chiral
environment about the reactive metal center.
[*] M. C. Wood, D. C. Leitch, C. S. Yeung, J. A. Kozak, Prof. L. L. Schafer
Department of Chemistry
The axially chiral diamine was prepared as a racemate and
subsequently resolved by using a modified published proto-
col.[11] Preliminary efforts focused on the preparation of the
(+) enantiomer of the proligands for an initial catalyst screen.
Reaction of the (+)-diamine with three equivalents of
mesitoyl chloride (a), naphthoyl chloride (b), or adamantoyl
chloride (c) in toluene, with pyridine as base, resulted in the
preparation of microcrystalline proligands that could be
purified by recrystallization in good yield (Scheme 1). These
new chiral proligands were fully characterized, including
determination of their specific rotations (e.g. for (+)-3a:
[a]2D0 = + 1398). The purified proligand was then dried under
The University of British Columbia
Vancouver, BC (Canada)
Fax: (+1)604-822-2847
E-mail: schafer@chem.ubc.ca
[**] This work was supported by Boehringer Ingelheim Canada, Ltd.,
and a matching NSERC CRD grant. M.W. and D.C.L. thank the UBC
and the Department of Chemistry for graduate fellowships. C.S.Y.
and J.A.K. thank the NSERC for summer undergraduate research
fellowships. The authors thank Robert K. Thomson and Brian O.
Patrick for assistance with X-ray crystallography.
Supporting information for this article (including all crystallo-
graphic and experimental details)is available on the WWW under
http://www.angewandte.org or from the author.
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Communications
Table 1: Screening of asymmetric hydroamination with precatalysts
4a–c.
vacuum and treated with one equivalent of Zr(NMe2)4 in
benzene as solvent. The solvent and dimethyl amine by-
product were removed under vacuum to give (+)-4a–c as light
yellow, highly soluble materials in over 90% yield
(Scheme 1). These solid crude materials were then screened
for catalyst activity and enantioselectivity in the cyclohy-
droamination of 2,2-diphenyl-4-pentenamine in [D8]toluene
on a small scale at 1108C (Table 1).
Complex (+)-4a showed high efficiency in the cyclo-
hydroamination reaction (Table 1, entry 1), with complete
conversion of the starting material to product occurring
within 75 min. The steric bulk imposed by the mesityl group
was the most significant in this series of amidate complexes,
and consequently the observed enantioselectivity of 74% ee
was the highest for this catalyst screen. Complex (+)-4b
(Table 1, entry 2) shows somewhat reduced reactivity, and at
present we attribute this to the comparably reduced steric
congestion imposed by the naphthyl substituent, which may
permit equilibria with aggregate
Entry
Precat.
Loading
[mol%]
t [h]
Conv. [%][a]
ee [%][b]
1
2
3
4
5
(+)-4a
(+)-4b
(+)-4c
(À)-4a
(+)-4a
10
10
10
10
5
1.25
18
3
1.25
2.5
>98 (93)[c]
>98
74 (R)[d]
31
>98
39
>98 (93)[c]
>98
72 (S)[d]
74
1
[a] Measured by H NMR spectroscopy. [b] Enantiomeric excess based
on 1H NMR spectroscopy of the product following derivatization with
(+)-(S)-a-methoxy-a-trifluoromethylphenylacetyl chloride. [c] Yield of
isolated product. [d] Absolute stereochemistry assigned based on
19F NMR spectroscopy of the (+)-(S)-a-methoxy-a-trifluoromethylphe-
nylacetyl chloride derivative[12]
species that are catalytically inac-
tive. Furthermore, the enantiose-
Table 2: Asymmetric hydroamination using precatalysts (+)-4a or (À)-4a (10 mol%)at 110 8C in
toluene.[a]
lectivity imparted by this catalyst
system is somewhat reduced at
31% ee. Finally, complex (+)-4c
with the bulky adamantyl substitu-
ent revealed good catalytic activity
(Table 1, entry 3), requiring 3 h for
the reaction to go to completion.
The steric bulk imposed by the
adamantyl group is significant, yet
this bulk lies removed from the
reactive metal center and may
explain the modest enantioselec-
tivity of 39% ee. Thus, by taking
advantage of the modular nature of
the amidate ligands, a rapid screen
was used to identify the first neu-
tral Zr complexes that mediate
enantioselective alkene hydroami-
nation of primary aminoalkenes.[4b]
Most importantly, the mesityl-sub-
stituted complex (+)-4a was found
to impart the highest enantioselec-
tive control. The enantiomer
obtained using (À)-4a was ach-
ieved with comparable enantiose-
lectivity (Table 1, entry 4). Finally,
the catalyst loading of (+)-4a
could be reduced to 5 mol% with
no detectable loss in enantioselec-
tivity (Table 1, entry 5), although
the reaction required double the
time to reach complete conversion.
With catalyst (+)-4a in hand,
Entry
Precat.
Aminoalkene
Product
t [h]
Yield [%][a]
ee [%]
1
(+)-4a
3
80[b]
93[c]
2
3
(À)-4a
(+)-4a
3
5
>98[d]
93[b]
88[b]
91
4
5
(+)-4a
(+)-4a
3
96
88
82[e]
74[e]
4.5
82
6
7
(+)-4a
(+)-4a
2
92:88[e]
62:86[b]
(2.3:1)[f]
94
12
(1.9:1)[f]
[a] Yield of isolated product unless otherwise noted. [b] Yield of isolated product following derivatization
with benzoyl chloride. [c] Enantiomeric excess based on 1H NMR spectroscopy of the product following
derivatization with (+)-(S)-a-methoxy-a-trifluoromethylphenylacetyl chloride. [d] Yield based on
1H NMR spectroscopy. [e] Enantiomeric excess based on 19F NMR spectroscopy of the (+)-(S)-a-
methoxy-a-trifluoromethylphenylacetyl chloride derivative[3] [f] Diastereomeric ratio.
investigations of its application in the preparation of isolable
gem-substituted heterocyclic products were undertaken
(Table 2). Reported ee values were determined by integration
of 1H and/or 19F NMR spectra of the (S)-Mosherꢀs acid
derivatives of at least two independent experiments. Remark-
ably, the smaller gem-dimethyl-substituted substrate was used
with (+)-4a (Table 2, entry 1) and the benzoyl-derivatized
pyrrolidine product was isolated in good yield with 93% ee.
To the best of our knowledge, this is the highest enantiose-
lectivity reported for this typical test substrate. Furthermore,
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we confirmed that the opposite enantiomer could be prepared
in 93% ee also by using (À)-4a (Table 2, entry 2). Precatalyst
(+)-4a efficiently formed spiro-pyrrolidine products in excel-
lent yield and with good enantioselectivity (Table 2, entries 3
and 4). Only the gem-disubstituted product was isolated in
good yield and no bicyclic products resulted from a second
intramolecular alkene hydroamination (Table 2, entry 5).[1a]
Good to excellent enantioselectivities were observed in the
preparation of diastereomeric products (Table 2, entries 6 and
7).[1a,14] While pyrrolidine products were formed with excel-
lent enantioselectivities in this first example of asymmetric
neutral Group 4 metal catalyzed alkene hydroaminations,
piperidine products were noted to be formed in excellent
yields (e.g. 91%) although with substantially reduced enan-
tioselectivies (e.g. 29% ee).[15] The lower ee values observed in
the formation of piperidines are consistent with a larger, less-
organized eight-membered transition state that would be
required in the metal-mediated formation of the six-mem-
bered ring product (see below).
The most active and enantioselective catalyst 4a was fully
characterized. Amorphous samples of (+)-4a isolated from
the reaction mixture gave 1H and 13C NMR spectra and
elemental analysis data that were consistent with the for-
mulation shown in Scheme 1.[15] The specific rotation of the
metal complex was determined as [a]2D0 = + 4228 in benzene.
Unfortunately, attempts to grow X-ray quality crystals of this
material from noncoordinating solvents failed. From a sample
of incompletely dried crude product, X-ray quality crystals of
the HNMe2 adduct of complex (+)-4a were obtained by
recrystallization from a pentane solution at room temper-
ature. The solid-state molecular structure (Figure 1) con-
firmed a monomeric species that is seven-coordinate, with a
distorted pentagonal-bipyramidal geometry. In the crystalline
material, a neutral dimethylamine ligand (N5) occupies an
axial position to give a coordinatively saturated 18-electron
complex. The tethered amidate ligand is in the equatorial
plane with the rigid chiral backbone defining a slight canting
of the auxiliary ligand.
Figure 1. Two views of an ORTEP diagram (ellipsoids shown at 50%
probability level)of the dimethylamine adduct of ( +)-4a (CH3 sub-
stituents omitted from N4 dimethylamido ligand for clarity in the top
view). Selected interatomic distances [Š] and angles [o]: Zr1–O1
2.2802(35), Zr1–O2 2.2890(37), Zr1–N1 2.3134(43), Zr1–N2
2.3468(33), Zr1–N3 2.0651(41), Zr1–N4 2.0694(43), Zr1–N5
2.5357(53); O1-Zr1-O2 166.68(0.13), N1-Zr1-N2 74.87(0.16), O1-Zr1-
N1 56.81(0/13), O2-Zr1-N2 56.21(0.13), N3-Zr1-N5 177.95(0.17), O1-
C1-N1 144.52(0.41), O2-C2-N2 113.47(0.42). Biphenyl torsion angle [o]:
68.28(0.65).
Scheme 2. Substrate scope test reaction which suggests that the
Preliminary efforts to probe the mechanism of this
important reaction confirmed that the activity and selectivity
of the catalyst remain unaffected by the presence of 2,6-di-
tert-butyl-4-methylpyridine (a bulky noncoordinating base)
thereby negating the possibility of proton-mediated cataly-
sis.[16] Furthermore, this precatalyst was tested with the
secondary-amine derivative of the most reactive substrate
(Scheme 2) and no heterocyclic product was observed by
1H NMR spectroscopy, despite prolonged reaction times (up
to 4 days) and elevated reaction temperatures (up to 1408C).
This is in contrast to the cationic catalysts with Group 4
metals that are unable to mediate the hydroamination of
primary aminoalkenes, but work efficiently with a range of
secondary aminoalkenes.[5,6] The lack of reactivity in our case
suggests that alkene hydroamination is mediated by the in situ
formation of a catalytically viable Zr imido complex, which
then undergoes a [2+2] cycloaddition reaction with the
alkene through a chairlike transition state. The proposed
cycloaddition reaction results in the formation of an azame-
tallacyclobutane intermediate. This imido-based mechanism
is well established for alkyne hydroaminations catalyzed by
mechanism involves a Zr imido complex.
Group 4 metals[8c,17] and has been postulated for alkene
hydroamination by ourselves and others.[14,18] Additionally,
we recently reported the first example of an isolable bis-
(amidate)Zr imido complex (with the amidates bound in the
equatorial plane and the imido group bound axially), which
was also a competent precatalyst for the hydroamination of
primary aminoalkenes.[10] Thus, by combining our mechanistic
rationale with structural data obtained for the precatalyst, we
propose the preferred formation of one of the diastereomeric
azametallacyclic intermediates as a result of steric interac-
tions with the geminal substituents, as shown in Figure 2.
Further experiments to study the substrate scope and kinetic
mechanistic investigations are underway to probe this work-
ing hypothesis.
In summary, we have illustrated the ease of synthesis and
flexibility afforded by the modular amidate ligand set and the
potential of this variable class of complexes in enantioselec-
tive cyclohydroaminations catalyzed by Group 4 metals.
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Communications
f) J. Collin, J.-C. Daran, O. Jacquet, E. Schulz, A. Trifonov,
Chem. Eur. J. 2005, 11, 3455; g) S. Hong, S. Tian, M. V. Metz, T. J.
Marks, J. Am. Chem. Soc. 2003, 125, 14768; h) P. N. OꢀShaugh-
nessy, P. D. Knight, C. Morton, K. M. Gillespie, P. Scott, Chem.
Commun. 2003, 1770; i) P. N. OꢀShaughnessy, P. D. Knight, C.
Morton, K. M. Gillespie, P. Scott, Tetrahedron: Asymmetry 2003,
14, 1979.
[4] a) D. J. Ramon, M. Yus, Chem. Rev. 2006, 106, 2126; b) An
independent report on work regarding an analogous project by
Bergman and co-workers was submitted simultaneously: D. A.
Watson, M. Chieu, R. G. Bergman, Organometallics, 2006,
ASAP.
[5] P. D. Knight, I. Munslow, P. N. OꢀShaughnessy, P. Scott, Chem.
Commun. 2004, 894.
[6] D. V. Gribkov, K. C. Hultzsch, Angew. Chem. 2004, 116, 5659;
Angew. Chem. Int. Ed. 2004, 43, 5542.
Figure 2. Suggested intermediates in the enantioselective aminoalkene
hydroamination using precatalyst (+)-4a in which the alkene can
approach from the Re face or the Si face.
[7] a) K. K. Hii, Pure Appl. Chem. 2006, 78, 341; b) N. T. Patil, L. M.
Lutete, H. Wu, N. K. Pahadi, I. D. Gridnev, Y. Yamamoto,J. Org.
Chem. 2006, 71, 4270; c) L. M. Lutete, I. Kadota, Y. Yamamoto,
J. Am. Chem. Soc. 2004, 126, 1622; d) S. Gischig, A. Togni, Eur. J.
Inorg. Chem. 2005, 4745; e) L. Fadini, A. Togni, Chem.
Commun. 2003, 30; f) O. Loeber, M. Kawatsura, J. F. Hartwig,
J. Am. Chem. Soc. 2001, 123, 4366; g) R. Dorta, P. Egli, F.
Zurcher, A. Togni, J. Am. Chem. Soc. 1997, 119, 10857.
[8] a) C. Li, R. K. Thomson, B. Gillon, B. O. Patrick, L. L. Schafer,
Chem. Commun. 2003, 2462; b) Z. Zhang, L. L. Schafer, Org.
Lett. 2003, 5, 4733; c) Z. Zhang, M. Lu, D. C. Leitch, B. O.
Patrick, L. L. Schafer, Chem. Eur. J., DOI: 10.1002/
chem.200600735.
These modular amidate complexes are easily prepared from
commercially available chiral diamines, acid chlorides, and
Zr(NMe2)4 to yield precatalysts that can be isolated on the
gram scale. Most importantly, these first examples of neutral
chiral zirconium precatalysts for enantioselective intramolec-
ular hydroamination show promising preliminary results,
providing ee values of up to 93%. Ongoing efforts are
focused on mechanistic investigations and on broadening the
scope of reactivity and selectivity of this class of complexes.
[9] R. O. Ayinla, L. L. Schafer, Inorg. Chim. Acta 2006, 359, 3097.
[10] R. K. Thomson, J. A. Bexrud, L. L. Schafer, Organometallics
2006, 25, 4069.
Received: July 26, 2006
Published online: October 9, 2006
[11] T. L. Marxen, B. J. Johnson, P. V. Nilsson, L. H. Pignolet, Inorg.
Chem. 1984, 23, 4663.
[12] a) R. K. Thomson, F. E. Zahariev, Z. Zhang, B. O. Patrick, Y. A.
Wang, L. L. Schafer, Inorg. Chem. 2005, 44, 8680; b) D. A.
Kissounko, I. A. Guzei, S. H. Gellman, S. S. Stahl, Organo-
metallics 2005, 24, 5208; c) B.-H. Huang, T.-L. Yu, Y.-L. Huang,
B.-T. Ko, C.-C. Lin, Inorg. Chem. 2002, 41, 2987.
[13] G. R. Giesbrecht, A. Shafir, J. Arnold, Inorg. Chem. 2001, 40,
6069.
[14] J. A. Bexrud, J. D. Beard, D. C. Leitch, L. L. Schafer, Org. Lett.
2005, 7, 1959.
Keywords: amidates · asymmetric catalysis · heterocycles ·
hydroamination · zirconium
.
[1] a) P. H. Martinez, K. C. Hultzsch, F. Hampel, Chem. Commun.
2006, 2221; b) K. C. Hultzsch, Adv. Synth. Catal. 2005, 347, 367;
c) K. C. Hultzsch, Org. Biomol. Chem. 2005, 3, 1819; d) P. W.
Roesky, T. E. Müller, Angew. Chem. 2003, 115, 2812; Angew.
Chem. Int. Ed. 2003, 42, 2708.
[15] See Supporting Information.
[2] a) A. L. Odom, Dalton Trans. 2005, 225; b) S. Hong, T. J. Marks,
Acc. Chem. Res. 2004, 37, 673; c) J. F. Hartwig, Pure Appl. Chem.
2004, 76, 507; d) F. Pohlki, S. Doye, Chem. Soc. Rev. 2003, 32,
104; e) J. Seayad, A. Tillack, C. G. Hartung, M. Beller, Adv.
Synth. Catal. 2002, 344, 795; f) J.-J. Brunet, D. Neibecker in
Catalytic Heterofunctionalization, Vol. 98 (Eds.: A. Togni, H.
Grützmacher), Wiley-VCH, Weinheim, 2001, p. 91; g) T. E.
Müller, M. Beller, Chem. Rev. 1998, 98, 675.
[3] a) N. Meyer, A. Zulys, P. W. Roesky, Organometallics 2006, 25,
4179; b) D. V. Gribkov, K. C. Hultzsch, F. Hampel, J. Am. Chem.
Soc. 2006, 128, 3748; c) D. Riegert, J. Collin, A. Meddour, E.
Schulz, A. Trifonov, J. Org. Chem. 2006, 71, 2514; d) K. C.
Hultzsch, D. V. Gribkov, F. Hampel, J. Organomet. Chem. 2005,
690, 4441; e) J. Y. Kim, T. Livinghouse, Org. Lett. 2005, 7, 1737;
[16] L. L. Anderson, J. Arnold, R. G. Bergman, J. Am. Chem. Soc.
2005, 127, 14542.
[17] a) A. Tillack, H. Jiao, I. G. Castro, C. G. Hartung, M. Beller,
Chem. Eur. J. 2004, 10, 2409; b) Y. Li, Y. Shi, A. L. Odom, J. Am.
Chem. Soc. 2004, 126, 1794; c) J. S. Johnson, R. G. Bergman, J.
Am. Chem. Soc. 2001, 123, 2923; d) F. Pohlki, S. Doye, Angew.
Chem. 2001, 113, 2361; Angew. Chem. Int. Ed. 2001, 40, 2305;
e) P. J. Walsh, A. M. Baranger, R. G. Bergman, J. Am. Chem.
Soc. 1992, 114, 1708; f) P. L. McGrane, M. Jensen, T. Living-
house, J. Am. Chem. Soc. 1992, 114, 5459.
[18] a) H. Kim, P. H. Lee, T. Livinghouse, Chem. Commun. 2005,
5205; b) B. F. Straub, R. G. Bergman, Angew. Chem. 2001, 113,
4768; Angew. Chem. Int. Ed. 2001, 40, 4632.
358
www.angewandte.org
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