2-Pyridonate titanium complexes for chemoselectivity. accessing intramolecular hydroaminoalkylation over hydroamination

Article abstract of DOI:10.1021/ol402890m

Chemoselectivity of intramolecular hydroaminoalkylation over hydroamination has been achieved with a bis(3-phenyl-2-pyridonate) titanium complex. Primary aminoalkenes are selectively α-alkylated by C-H functionalization adjacent to nitrogen to access five

Full text of DOI:10.1021/ol402890m

ORGANIC
LETTERS
2013
Vol. 15, No. 23
6002–6005
2‑Pyridonate Titanium Complexes
for Chemoselectivity. Accessing
Intramolecular Hydroaminoalkylation
over Hydroamination
Eugene Chong and Laurel L. Schafer*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver,
British Columbia, Canada V6T 1Z1
schafer@chem.ubc.ca
Received October 7, 2013
ABSTRACT
Chemoselectivity of intramolecular hydroaminoalkylation over hydroamination has been achieved with a bis(3-phenyl-2-pyridonate) titanium
complex. Primary aminoalkenes are selectively R-alkylated by CÀH functionalization adjacent to nitrogen to access five- and six-membered
cycloalkylamines with a good substrate-dependent diastereoselectivity of up to 19:1.
The development of efficient synthetic routes to amines
is highly desired due to their prevalence in biologically
active compounds and a vast majority of drugs. An emerg-
ing catalytic CÀH functionalization method to access
higher substituted amines is hydroaminoalkylation,1 the
addition of an sp3-hybridized R-CÀH bond adjacent to
nitrogen across a CdC bond (Scheme 1). This atom-
economic CÀC bond forming reaction has been observed
as an unexpected byproduct2 of intramolecular hydroami-
nation,3 a CÀN bond forming reaction from the addition
of an NÀH bond across a CdC bond. Both early (groups 4
and 5)2,4À6 and late (Ir and Ru)7 transition metal catalysts
are able to catalyze the CÀC bond forming reaction. The
usage of early transition metals2,4À6 could be advanta-
geous due to their low toxicity and cost and the fact that
unprotected amines can be used as substrates.8
(6) For group 5 metal catalysts, see: (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)
Eisenberger, P.; Schafer, L. L. Pure Appl. Chem. 2010, 82, 1503. (g) Zi,
G.; Zhang, F.; Song, H. Chem. Commun. 2010, 46, 6296. (h) Zhang, F.;
Song, H.; Zi, G. Dalton Trans. 2011, 40, 1547. (i) Reznichenko, A. L.;
€
Emge, T. J.; Audorsch, S.; Klauber, E. G.; Hultzsch, K. C.; Schmidt, B.
Organometallics 2011, 30, 921. (j) Reznichenko, A. L.; Hultzsch, K. C. J.
Am. Chem. Soc. 2012, 134, 3300. (k) Payne, P. R.; Garcia, P.; Eisenber-
ger, P.; Yim, J. C.-H.; Schafer, L. L. Org. Lett. 2013, 15, 2182. (l) Garcia,
P.; Payne, P. R.; Chong, E.; Webster, R. L.; Barron, B. J.; Behrle, A. C.;
Schmidt, J. A. R.; Schafer, L. L. Tetrahedron 2013, 69, 5737. (m) Garcia,
P.; Lau, Y. Y.; Perry, M. R.; Schafer, L. L. Angew. Chem., Int. Ed. 2013,
52, 9144. (n) Zhang, Z.; Hamel, J.-D.; Schafer, L. L. Chem.;Eur. J.
2013, 19, 8751.
(1) For a review of hydroaminoalkylation, see: Roesky, P. W. Angew.
Chem., Int. Ed. 2009, 48, 4892.
€
(2) Muller, C.; Saak, W.; Doye, S. Eur. J. Org. Chem. 2008, 2731.
€
(3) For a review of hydroamination, see Muller, T. E.; Hultzsch,
K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795 and
references therein.
€
(4) For Ti catalysts, see: (a) Prochnow, I.; Zark, P.; Muller, T.; Doye,
S. Angew. Chem., Int. Ed. 2011, 50, 6401. (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. ChemCatChem 2009,
1, 162. (d) Kubiak, R.; Prochnow, I.; Doye, S. Angew. Chem., Int. Ed.
2010, 49, 2626. (e) Jaspers, D.; Saak, W.; Doye, S. Synlett 2012, 23, 2098.
(f) Dorfler, J.; Doye, S. Angew. Chem., Int. Ed. 2013, 52, 1806. (g) Preuss,
T.; Saak, W.; Doye, S. Chem.;Eur. J. 2013, 19, 3833.
(5) For a Zr catalyst, see: Bexrud, J. A.; Eisenberger, P.; Leitch, D. C.;
(7) For Ru and Ir catalysts, see: (a) Jun, C.-H.; Hwang, D.-C.; Na,
S.-J. Chem. Commun. 1998, 1405. (b) Chatani, N.; Asaumi, T.; Yor-
imitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001,
123, 10935. (c) Pan, S.; Endo, K.; Shibata, T. Org. Lett. 2011, 13, 4692.
ꢀ
(d) Bergman, S. D.; Storr, T. E.; Prokopcova, H.; Aelvoet, K.; Diels, G.;
€
Meerpoel, L.; Maes, B. U. W. Chem.;Eur. J. 2013, 18, 10393. (e) Pan,
S.; Matsuo, Y.; Endo, K.; Shibata, T. Tetrahedron 2012, 68, 9009.
(8) Pyridyl-substitution on the amine is required as a directing group
for late transition metal examples.
Payne, P. R.; Schafer, L. L. J. Am. Chem. Soc. 2009, 131, 2116.
r
10.1021/ol402890m
Published on Web 11/13/2013
2013 American Chemical Society

promotes hydroamination (3) over hydroaminoalkyla-
tion (2) with intramolecular substrate 1.2 Our previously
reported Zr pyridonate complex 4 is a good catalyst
for substrate controlled intramolecular hydroamino-
alkylation,5 but with 1, it also promotes hydroamina-
tion preferentially, as only 3 was observed.10 Further-
more, our reported N,O-chelated Ta intermolecular
hydroaminoalkylation catalysts, 5,6e,f,k and 6,6m as well
as TaMe3Cl2,6n and Hultzsch’s binaphtholate system
7,6i give only 3 as the product. Given that only Ti
showed promise for the formation of 2, Ti was chosen
for further investigation.
Scheme 1. Hydroaminoalkylation
While intermolecular hydroaminoalkylation has been
achieved with group 5 metals6 and Ti catalysts,4bÀg the
intramolecular variant2,4aÀ4c,5 of the reaction remains un-
derdeveloped. To date, limitations include a narrow sub-
strate scope due to hydroamination byproduct formation,
low diastereoselectivity, high reaction temperatures (130À
160 °C), and long reaction times (up to 96 h). Despite the
fact that group 5 systems are able to catalyze the inter-
molecular transformation with a broad substrate scope
and can even mediate asymmetric catalytic reactions,6eÀj
such reactivity has not yet been realized for the intra-
molecular reaction.6 Rather, previously reported group
5 intermolecular hydroaminoalkylation catalysts, based
on biaryldiamine6h or binaphtholate6i ligands for example,
have been shown to give the intramolecular hydroamina-
tion products instead. When targeting hydroaminoalkyla-
tion over hydroamination reactivity the high energetic
barrier of intermolecular hydroamination ensures that
there is no unwanted hydroamination in the intermolecu-
lar variant of the reaction.9 However, in the case of the
intramolecular reaction, the hydroamination route is
more energetically feasible and typically dominates over
hydroaminoalkylation.
Scheme 2. Comparison of Reported Groups 4 and 5 Precatalysts
for both Hydroaminoalkylation (HAA) and Hydroamination
(HA) Reactions
Currently, only a handful of group 4 systems, Ti-
(NMe2)4,2,4aÀ4c Ind2TiMe2,2 TiBn4,4c and bis(6-tert-butyl-
3-phenyl-2-pyridonate) Zr complex 4,5 are known to be
reactive for intramolecular hydroaminoalkylation. These
catalytic systems have relied on substrate controlled reac-
tivity such that the favorable six-membered-ring hydro-
aminoalkylation (HAA) product is formed over the
challenging seven-membered-ring hydroamination (HA)
product. It is desirable to develop catalyst controlled
selectivity to access hydroaminoalkylation products pre-
ferentially. Herein, we disclose catalyst development ef-
forts to realize the first example of a Ti catalyst that is
chemoselective for intramolecular hydroaminoalkylation
over hydroamination.
Aminoalkene 1 is a common substrate for hydroamina-
tion that is resistant to hydroaminoalkylation (Scheme 2).
Thus, it is a good test substrate for examining catalyst con-
trolled selectivity for hydroaminoalkylation over hydro-
amination. A survey of known group 4 and 5 complexes
shows that the formation of the hydroaminoalkylation
product 2 over the hydroamination product 3 is rarely
observed (Scheme 2). Of these screened complexes, only
Ti(NMe2)4 shows the formation of 2 in modest quantities,2
whereas Zr(NMe2)4 and Hf(NMe2)4 give only the forma-
tion of 3. While Ind2TiMe2 is a useful catalyst for the
intermolecular hydroaminoalkylation of alkenes,4d,g it
a Determined by 1H NMR spectroscopy using 1,3,5-trimethoxyben-
zene as an internal standard. b 5 mol %, 105 °C. c 10 mol %, 5 h. d 5 mol %,
120 °C, 36 h, C6D6.
Initial investigations focused on exploring the reactivity
of N,O- and N,N-chelated Ti complexes for reactivity with
substrate 1 (Table 1). Related ligand sets have been
employed for the development of intermolecular hydro-
aminoalkylation precatalysts.4e,f,5,6eÀh,6kÀm A screening
of amidate complexes11,12 (Table 1, entries 1 and 2) and a
ureate complex13 (Table 1, entry 3) shows that simple
amidate and ureate ligand sets are not good for intramo-
lecular hydroaminoalkylation, as only hydroamination
product 3 is observed. A bulky mono(2-aminopyridinate)
complex14 also gives 3 as the only product (Table 1, entry 4).
However, using 2-aminopyridinate complexes generated
(10) Bexrud, J. A.; Schafer, L. L. Dalton Trans. 2010, 39, 361.
(11) Webster, R. L.; Noroozi, N.; Hatzikiriakos, S. G.; Thomson,
J. A.; Schafer, L. L. Chem. Commun. 2013, 49, 57.
(12) Thomson, R. K.; Zahariev, F. E.; Patrick, B. O.; Wang, Y. A.;
Schafer, L. L. Inorg. Chem. 2005, 44, 8680.
(13) Leitch, D. C.; Beard, J. D.; Thomson, R. K.; Wright, V. A.;
Patrick, B. O.; Schafer, L. L. Eur. J. Inorg. Chem. 2009, 2691.
(14) Chong, E.; Qayyum, S.; Schafer, L. L.; Kempe, R. Organome-
tallics 2013, 32, 1858.
(9) Currently, there is no report of group 4 or 5 metal catalyzed
intermolecular hydroamination in the literature.
Org. Lett., Vol. 15, No. 23, 2013
6003

in situ with less sterically demanding N-methyl-2-amino-
pyridine4f shows that a 1:2 mixture of Ti(NMe2)4 and the
proligand is more selective for hydroaminoalkylation
than a 1:1 mixture (Table 1, entry 5). To extend our
investigation of 2-pyridonate group 4 complexes5,10,11
and modify 4 for enhanced reactivity, bis(2-pyridonate) Ti
complexes have been synthesized by reacting Ti(NMe2)4
with various 2-pyridones (2 equiv), and crude products15
have been used for catalytic screening (Table 1, entries
6À13). The Ti analogue of 4 with bulky 3,6-disubstituted
pyridonates shows poor reactivity (Table 1, entry 6).
Some steric bulk promotes favorable reactivity, as simple
2-pyridonate shows a preference for hydroaminoalkyla-
tion over hydroamination, but low conversion is observed
with unidentified side products (Table 1, entry 7). The
location of the steric bulk is shown to be critical.
6-Methylpyridonate (Table 1, entry 8) is unfavorable,
while 3-methylpyridonate (Table 1, entry 9) increases
conversion to the desired hydroaminoalkylation products.
To our delight, 3-phenylpyridonate shows a dramatic
improvement in selectivity for hydroaminoalkylation
(Table 1, entry 10). Increasing the steric bulk at position
3 with a mesityl substituent disfavors reactivity (Table 1,
entry 11). In probing the importance of electronic
effects, an electron-donating 4-methoxyphenyl substitu-
ent (Table 1, entry 12) shows negligible influence on
hydroaminoalkylation reactivity over the phenyl substi-
tuent (Table 1, entry 10), but an electron-withdrawing
3,5-difluorophenyl substituent increases the unwanted
hydroamination reactivity (Table 1, entry 13).
Table 1. Screening of N,O- and N,N-Ligands on Titaniuma
With 3-phenyl-2-pyridonate chosen as the ideal ligand
for the reaction, the bis(2-pyridonate) Ti complex 8 has
been synthesized (vide supra) and characterized.16 The
solid-state molecular structure of 8 reveals an O-trans
C2-symmetric structure with a distorted octahedral coor-
dination about the Ti center and both ligands bound in a
κ2-binding mode (Figure 1). Asymmetric binding of the
˚
˚
N,O-ligand [TiÀOavg 2.0268(12) A; TiÀNavg 2.2567(14) A]
is observed,16 in agreement with previously reported 2-pyr-
idonate group 4 complexes.5,10,11
a [Substrate] = 0.25 M. b Determined by 1H NMR spectroscopy
using 1,3,5-trimethoxybenzene as an internal standard. n.d. = not
determined. c LTi(NMe2)3. d In situ prepared complex. e Using a 1:1
mixture of Ti(NMe2)4 and LH.
Complex 8 displays catalyst controlled preferential for-
mation of both five- and six-membered cycloalkylamines
from primary aminoalkenes, rather than N-heterocyclic
hydroamination products (Table 2). An overall catalyst
loading of 20mol % is added in two batches of 10mol % to
overcome the observed slow decomposition of catalyst
over the course of the reaction.17 Good reactivity of 8 at
temperatures as low as 110 °C is feasible, in comparison to
Ti(NMe2)4 and TiBn4 that require temperatures in the
range of 130À160 °C.4aÀc For the synthesis of cyclopentyl-
amines (Table 2, entries 1À3), the cis diastereomer is
formed preferentially with good selectivity (up to 10:1).
This compares favorably with previous reports (dr = 4:1)
where the hydroaminoalkylation products are observed
Figure 1. ORTEP representation of the solid-state molecular
structure of 8 plotted with 50% probability ellipsoids for non-
hydrogen atoms. Benzene solvent molecule omitted for clarity.
(15) Crude complexes are of sufficient purity, and 1H NMR spectra
show single products.
(16) See Supporting Information.
(17) Monitoring of the reaction as a function of time shows a marked
decrease in the rate of conversion over time.
only as side products of hydroamination.2 Impressively,
disubstituted alkenes can undergo hydroaminoalkylation
6004
Org. Lett., Vol. 15, No. 23, 2013

Table 2. Intramolecular Hydroaminoalkylation of Primary
Aminoalkenes with 8a
Scheme 3. Evaluation of Secondary Aminoalkene Substrates
and Effect of Catalyst Concentration with 8
catalyst concentration further increases the chemoselectivity
for hydroaminoalkylation over hydroamination (Scheme 3,
eq 2). These observations are consistent with the pre-
viously reported formation of dimeric imido species,
which are proposed to be unreactive for hydroamination,
but may promote hydroaminoalkylation via bridging
metallaziridine intermediates.5,16
In summary, we have shown for the first time that
intramolecular hydroaminoalkylation of primary ami-
noalkenescan beachieved selectivelyover hydroamination
using bis(3-phenyl-2-pyridonate) Ti complex 8 to access
both five- and six-membered cycloalkylamines. Further-
more, a noticeable improvement in diastereoselectivity of
up to 19:1 has been realized by utilizing the small Ti metal
center in combination with 3-substituted-2-pyridonate
ligands. Mechanistic investigations are currently ongoing
to elucidate reactive intermediates and rationalize the
observed diastereoselectivities of the reaction. These
mechanistic insights will assist in the development of
new catalysts with enhanced catalytic efficiency and
stereoselectivities.
a Reaction conditions: substrate (0.60 mmol), 8 (2 Â 10 mol %),
toluene (2.4 mL), 110 °C, t = 48 h. b Isolated yield. c Determined by 1H
NMR spectroscopy prior to chromatography. d Yield of combined
diastereomers. e Yield of diastereomer illustrated. f Derivatized prior
to isolation. g 130 °C. h 145 °C.
Acknowledgment. We gratefully acknowledge NSERC,
ACS PRF, and Bayer CropScience for supporting this
work. We thank Jacky C.-H. Yim (UBC) and Dr. Brian O.
Patrick (UBC) for assistance with X-ray crystallography
and Dr. Mark Ford (Bayer CropScience) for helpful
discussions. E.C. thanks NSERC for a PGSD award. This
work was undertaken, in part, thanks to funding from the
Canada Research Chairs program.
intramolecularly for the first time (Table 2, entry 4).
Interestingly, the formation of the trans isomer is favored
in the formation of 1-aminoindane (Table 2, entry 5). For
the synthesis of cyclohexylamines (Table 2, entries 6À8),
excellent diastereoselectivity (up to 19:1) for the trans
isomer is observed. These results are a significant enhance-
ment over previously reported results (dr < 5:1).4c,5
It was noted that secondary N-methyl or N-phenyl
aminoalkene substrates are unreactive with 8 at 110 °C
or at 145 °C (Scheme 3, eq 1). This observation suggests
that Ti imido species could be involved as intermediates in
the catalytic cycle, as has been proposed for the related
Zr(2-pyridonate) complexes.5 Furthermore, an increase in
Supporting Information Available. Experimental details,
characterization data, and CIF file. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 23, 2013
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