In Situ Generation of a Regio- and Diastereoselective Hydroaminoalkylation Catalyst Using Commercially Available Starting Materials

Article abstract of DOI:10.1021/acs.orglett.7b02149

The design of an easy to use catalyst system for the regio- and diastereoselective intermolecular hydroaminoalkylation of alkenes with secondary amines is reported. The method utilizes commercially available ligands and tantalum starting materials, and does not require the isolation of air and water sensitive organometallic complexes. The in situ prepared catalyst is active toward a variety of secondary amine substrates, including those with ethyl substituents which yield α- and β-alkylated amines as a single diastereomer. This catalytic transformation can be used to prepare amines containing functionality that promotes ring closure to achieve the diastereoselective synthesis of di- and trialkylated N-heterocycles.

Full text of DOI:10.1021/acs.orglett.7b02149

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
In Situ Generation of a Regio- and Diastereoselective
Hydroaminoalkylation Catalyst Using Commercially Available
Starting Materials
Peter M. Edwards and Laurel L. Schafer*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada V6T 1Z1
S
* Supporting Information
ABSTRACT: The design of an easy to use catalyst system for the regio- and diastereoselective intermolecular
hydroaminoalkylation of alkenes with secondary amines is reported. The method utilizes commercially available ligands and
tantalum starting materials, and does not require the isolation of air and water sensitive organometallic complexes. The in situ
prepared catalyst is active toward a variety of secondary amine substrates, including those with ethyl substituents which yield α-
and β-alkylated amines as a single diastereomer. This catalytic transformation can be used to prepare amines containing
functionality that promotes ring closure to achieve the diastereoselective synthesis of di- and trialkylated N-heterocycles.
mines have a vast array of applications, from pharmaceut-
icals,1 to agrochemicals,2−4 and materials.5−8 Conse-
catalyst development: laborious ligand syntheses,14,17,18,24
handling of highly reactive metal precursors,25,26 and use of
isolated precatalysts (Figure 1). Here we show that these
challenges can be resolved through the development of a catalyst
system that can be assembled in situ from commercially available
starting materials using traditional syringe techniques.
Our group has developed several rigorously characterized
hydroaminoalkylation precatalysts (Figure 1), and the proligands
L1, L2, L3 required for their generation are shown in Figure
2.27,14,26 These same proligands were tested for in situ generation
of precatalysts, and the subsequent catalytic activity for the
hydroaminoalkylation benchmark reaction of 1-octene with N-
methylaniline is shown in Table 1. In situ catalyst preparation is
achieved using a simple protonolysis reaction between Ta-
(NMe2)5 and the respective proligand at room temperature for
15 min.
A
quently, catalytic methods for amine synthesis are an ongoing
area of research. Significant effort has gone into the development
of catalytic C−N bond forming reactions that utilize readily
available alkene and alkyne feedstocks, including hydroamination
or hydroformylation followed by reductive amination
(hydroaminomethylation).9−13 Notably, the synthesis of selec-
tively substituted amines with alkenes can also be achieved
through hydroaminoalkylation (Scheme 1).14−20 This C−H
Scheme 1. Regioselective Hydroaminoalkylation Reaction
The modest reaction temperature of 110 °C was selected to
facilitate the use of toluene as solvent. As shown in entry 1,
commercially available Ta(NMe2)5 alone proved to be a poor
catalyst under these conditions; however, the addition of an N,O-
chelating ligand drastically increased conversion (Table 1, entries
2−13). It is worth noting that the use of an in situ prepared
catalyst is identical to employing the isolated precatalyst (Table
1, entries 2−3 and 4−5). The use of the amide L1 increased
conversion to 87% within 24 h, while both pyridones L2 and L3
alkylation reaction allows for the synthesis of α- and β-alkylated/
arylated secondary amines. This catalytic method forms a
C(sp3)−C(sp3) bond α to an amine by addition of a C−H bond
across a CC bond of activated and unactivated alkenes, while
avoiding the use of protecting groups, photoredox catalysts, or
exogenous oxidants. This reaction can be catalyzed by early
transition metals, which are inexpensive, and the relevant starting
materials are commercially available.21−23
Early transition metal catalyzed hydroaminoalkylation has the
potential to be a powerful synthetic tool, and ongoing research
efforts for this reaction aim to address the following challenges in
Received: July 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02149
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
commercially available while L1 and L2 must be synthesized, L3
was selected for further development.
A reduction in the reaction temperature from 110 to 90 °C
resulted in a significantly reduced yield (Table 1, entry 8).
Likewise a reduction in the catalyst loading to only 2.5 mol %
resulted in a significant reduction in yield within the desired 24 h
time frame of the experiment (Table 1, entry 9). It was also
discovered that allowing the ligand and Ta(NMe2)5 to react prior
to addition of the substrates is important for reducing the
reaction time, increasing the 16 h conversion from 13% (Table 1,
entry 10) to 87% (Table 1, entry 11). An additional benefit of L3
is that it is soluble in toluene, allowing for the use of stock
solutions of both proligand and Ta(NMe2)5 and thus increasing
the ease of reaction setup in either the glovebox or using routine
syringe techniques. The proposed mechanism of this reaction is
shown in Figure 3.
Figure 1. Comparison of in situ formed pyridonate catalyst with
previously reported hydroaminoalkylation catalysts.
Figure 2. N,O-Proligands used for in situ catalyst synthesis.
Table 1. In Situ Catalyst Screening and Optimizationa
c
entry
ligand
temp (°C)
time (h)
conv (%)b
yield (%)
1
none
L1d
L1
110
110
110
110
110
110
100
90
24
16
N/A
N/A
N/A
N/A
N/A
95
Figure 3. Proposed hydroaminoalkylation mechanism.
2
24
87
3
24
87
As shown in Figure 3, precatalyst activation to form A is
accompanied by dimethylamine elimination. This dimethyl-
amine can then become a substrate for the reaction, and thus a
byproduct that is often observed is the product of the bis-
alkylation of dimethylamine (Scheme 2).29
d
4
L2
24
100
100
100
95
5
L2
L3
L3
L3
L3
L3
L3
L3
L3
24
6
24
7
24
90
8
24
26
21
9
110
110
110
110
110
24e
16
41
35
Scheme 2. Formation of Dimethylamine Byproduct
10
11
12
13
13
7
16f
16f,g
16h
87
82
100
96
96
91
a
This byproduct not only increases the amount of alkene
necessary to realize full conversion of the added amine substrate
but also can complicate reaction purification. Given the low
boiling point of dimethylamine, unwanted byproduct could be
eliminated by drastically increasing the headspace within the
sealed reaction vessel; either a 20 mL scintillation vial (glovebox
setup) (Table 1, entry 12) or a three-neck flask with an oil
bubbler outlet (syringe technique setup) (Table 1, entry 13)
offer optimized product yields. The prevention of byproduct
formation also leads to an increase in the relative rate of
conversion, with reactions being complete within 16 h rather
than 24 h (Table 1, entries 12 and 13). Prevention of byproduct
formation also simplifies the workup and product purification;
Reaction performed in a J-Young tube with 5 mol % [Ta] and 5 mol
b
% ligand unless stated otherwise. Determined by 1H NMR
spectroscopy through relative integration of ortho-aniline peaks.
c
d
e
f
Isolated yield. Isolated catalyst used. 2.5 mol % catalyst. Ligand
and [Ta] allowed to stir for 15 min prior to addition of substrates.
g
h
Reaction performed in a 20 mL vial with a PTFE cap. Reaction
performed on 1 g scale with 0.0825 M stock solution of catalyst in a
three-necked flask.
(Table 1, entry 6) led to full conversion. Ligands L2 and L3 also
benefit from selectively forming the monoligated complex,28
which allows for the in situ formation of the catalytic species while
avoiding less active bis-ligated complexes.14 Given that L3 is
B
DOI: 10.1021/acs.orglett.7b02149
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
after reaching 100% conversion, analytically pure product can be
obtained without column chromatography.
With optimized conditions in hand (Table 1, entry 12), several
different secondary amine substrates were tested (Scheme 3).
tantallaziridine A leads to the formation of the aza-metallacycle
B, with the substituents in the trans configuration instead of the
cis configuration (C) in order to minimize the steric repulsion of
the substituents of the metallacycle. Thus, using this one-step
catalytic reaction, α,β-alkylated amines and α,β′-heterocycles can
be prepared diastereoselectively.
Scheme 3. Amine Substrate Scope
Various alkenes were also tested for activity (Scheme 4).
Substituted styrenes 4a, 4i−j were tolerated, but with some
Scheme 4. Alkene Substrate Scope
a
10 mol % catalyst, 130 °C, 24 h.
Functionalized aniline derivatives can be tolerated (3b−3f),
although the inclusion of an alkyne 3i led to poor reactivity.
Ortho substituents on the phenyl ring led to a significant decrease
in yield (3d), likely due to the increased steric bulk surrounding
the nitrogen. Substrates with highly polar or protic functional
groups, such as ketones and hydroxyl groups, were not tolerated,
but dialkylamines 3j were reactive under more forcing
conditions.
a
10 mol % catalyst, 130 °C, 24 h.
Notably, both N-ethylaniline 3g and tetrahydroquinoline 3h
were useful substrates for the generation of a single diastereomer,
albeit under more forcing reaction conditions. This in situ
prepared catalyst is the first reported instance of hydro-
aminoalkylation with N-ethylaniline (Figure 4). This diaster-
eoselectivity can be explained through the proposed mechanism
of the reaction (Figure 3);30 insertion of the alkene into
sensitivity to steric bulk in the ortho-position. This sensitivity to
steric bulk on the alkene also results in internal alkenes and
geminally disubstituted alkenes not being tolerated, regardless of
reaction temperature.
Furthermore, various unactivated olefins were tolerated,
including those with protected functional groups such as acetals
4d, ketals 4e, and TBS-protected ethers 4f−g. Such functional
group tolerance is notable, as it allows for functional group
transformations for further synthetic elaboration, including the
preparation of unsaturated N-heterocyclic compounds, such as
piperidines (Scheme 5).31
Using our in situ prepared catalyst system, selectively alkylated
PMP-protected piperidine products can be assembled in two
synthetic steps. The aminoalcohol derivative 4l can be
deprotected and cyclized in a one-pot method using tosyl
fluoride to produce the cis-dimethylated piperidine product 5a in
excellent yield.31 As an alternative proof of concept, acidic
deprotection of ketal 4k leads to the formation of a cyclic imine,
which upon reduction with sodium cyanoborohydride gives the
2,3,6-methylated product 5b. These rapidly assembled alkylated
Figure 4. ORTEP representation of 3g-Oxalate X-ray crystallographic
structure. Ellipsoids plotted at 50% probability; nontertiary hydrogens
omitted for clarity.
C
DOI: 10.1021/acs.orglett.7b02149
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Sustainable Synthesis for funding, and P.E. thanks the University
of British Columbia for scholarship funding. This was supported
in part by the Canada Research Chairs program.
Scheme 5. Formation of Polysubstituted Piperidines
REFERENCES
■
(1) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W.
Chem. Soc. Rev. 2016, 45, 546−576.
(2) Nauha, E.; Nissinen, M. J. Mol. Struct. 2011, 1006, 566−569.
(3) Bean, M. J.; Ramsay, J. Agrochemical composition containing
activity-enhancing adjuvants. Google Patents: 2002.
(4) Lei, Y. J. ASTM Int. 2005, 2, 12172.
(5) Perry, M. R.; Ebrahimi, T.; Morgan, E.; Edwards, P. M.;
Hatzikiriakos, S. G.; Schafer, L. L. Macromolecules 2016, 49, 4423−4430.
(6) Lienkamp, K.; Madkour, A. E.; Musante, A.; Nelson, C. F.;
Nusslein, K.; Tew, G. N. J. Am. Chem. Soc. 2008, 130, 9836−9843.
̈
(7) Zheng, Z.-J.; Liu, L.-X.; Gao, G.; Dong, H.; Jiang, J.-X.; Lai, G.-Q.;
Xu, L.-W. RSC Adv. 2012, 2, 2895−2901.
(8) Kobayashi, S.; Song, J.; Silvis, H. C.; Macosko, C. W.; Hillmyer, M.
A. Ind. Eng. Chem. Res. 2011, 50, 3274−3279.
(9) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem.
̈
heterocycles are precursors to free piperidine building blocks via
oxidative cleavage of the 4-methoxyphenyl group.
Rev. 2008, 108, 3795−3892.
(10) Crozet, D.; Urrutigoïty, M.; Kalck, P. ChemCatChem 2011, 3,
1102−1118.
(11) Ren, T.; Patel, M.; Blok, K. Energy 2006, 31, 425−451.
(12) Meng, J.; Li, X.-H.; Han, Z.-Y. Org. Lett. 2017, 19, 1076−1079.
(13) Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. J. Chem.
Rev. 2015, 115, 2596−2697.
(14) Eisenberger, P.; Ayinla, R. O.; Lauzon, J. M. P.; Schafer, L. L.
Angew. Chem., Int. Ed. 2009, 48, 8361−8365.
(15) Herzon, S. B.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 14940−
14941.
In summary, an easy to use protocol for the in situ preparation
of a regioselective and diastereoselective tantalum hydroamino-
alkylation catalyst has been developed. This method utilizes
commercially available starting materials and does not require
the isolation of air- or moisture-sensitive organometallic
complexes. By modifying the reaction conditions we have
shown that undesirable byproduct formation, resulting from
dimethylamine hydroaminoalkylation, can be avoided. This
experimental procedure results in the synthesis of α- and β-
alkylated amines, providing a complementary disconnection
strategy for the synthesis of selectively substituted amines. We
have shown that the reaction can accommodate a variety of
different substrates, including N-ethylaniline and tetrahydro-
quinoline to give α,β-alkylated products diastereoselectively.
This early transition metal catalyst can be used in combination
with protected functionalities, thereby allowing for the synthesis
of polyalkylated unsaturated N-heterocycles. This early stage
work provides a platform for the further development of broadly
applicable and user-friendly early transition metal hydroamino-
alkylation catalysts.
(16) Reznichenko, A. L.; Hultzsch, K. C. J. Am. Chem. Soc. 2012, 134,
3300−3311.
(17) Dorfler, J.; Preuß, T.; Schischko, A.; Schmidtmann, M.; Doye, S.
̈
Angew. Chem., Int. Ed. 2014, 53, 7918−7922.
(18) Chong, E.; Brandt, J. W.; Schafer, L. L. J. Am. Chem. Soc. 2014,
136, 10898−10901.
(19) Zi, G.; Zhang, F.; Song, H. Chem. Commun. 2010, 46, 6296−6298.
(20) Weers, M.; Luhning, L. H.; Luhrs, V.; Brahms, C.; Doye, S. Chem. -
̈
̈
Eur. J. 2017, 23, 1237−1240.
(21) Tran, A.; Yu, J.-Q. Angew. Chem., Int. Ed. 2017, 56, 10530.
(22) Pan, S.; Endo, K.; Shibata, T. Org. Lett. 2011, 13, 4692−4695.
(23) Schinkel, M.; Wang, L.; Bielefeld, K.; Ackermann, L. Org. Lett.
2014, 16, 1876−1879.
(24) Manßen, M.; Lauterbach, N.; Dorfler, J.; Schmidtmann, M.; Saak,
̈
ASSOCIATED CONTENT
* Supporting Information
■
W.; Doye, S.; Beckhaus, R. Angew. Chem., Int. Ed. 2015, 54, 4383−4387.
(25) Zhang, Z.; Hamel, J.-D.; Schafer, L. L. Chem. - Eur. J. 2013, 19,
8751−8754.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02149.
(26) Garcia, P.; Lau, Y. Y.; Perry, M. R.; Schafer, L. L. Angew. Chem., Int.
Ed. 2013, 52, 9144−9148.
Crystallographic data for compounds 3g and 5 (CIF)
General experimental procedures, characterization details,
and 1H and 13C NMR spectra of compounds (PDF)
(27) Chong, E.; Garcia, P.; Schafer, L. L. Synthesis 2014, 46, 2884−
2896.
(28) Brandt, J.; Chong, E.; Schafer, L. L. ACS Catal. 2017, 7, 6323.
(29) Lauzon, J. M. P.; Eisenberger, P.; Rosca, S.-C.; Schafer, L. L. ACS
Catal. 2017, 7, 5921.
(30) Nugent, W. A.; Ovenall, D. W.; Holmes, S. J. Organometallics
1983, 2, 161−162.
(31) Payne, P. R.; Garcia, P.; Eisenberger, P.; Yim, J. C. H.; Schafer, L.
L. Org. Lett. 2013, 15, 2182−2185.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: schafer@chem.ubc.ca.
ORCID
Laurel L. Schafer: 0000-0003-0354-2377
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Damon Gilmour (University of British Columbia) for
support with X-ray crystallography. We thank National Sciences
and Engineering Resource Council (NSERC) and CREATE
D
DOI: 10.1021/acs.orglett.7b02149
Org. Lett. XXXX, XXX, XXX−XXX