Anti-Markovnikov Intermolecular Hydroamination: A Bis(amidate) Titanium Precatalyst for the Preparation of Reactive Aldimines

Article abstract of DOI:10.1021/ol0359214

(Matrix presented) A bulky bis-(N-2′,6′- diisopropylphenyl(phenyl)-amidate)titanium-bis(diethylamido) complex was identified as a highly active and regioselective precatalyst for the anti-Markovnikov hydroamination of a wide range of terminal alkyl alkynes with alkylamines. This titanium complex was fully characterized, including its X-ray crystal structure. The reactive aldimine products generated have been further elaborated using one-pot procedures to give substituted amines, aldehydes, and the isoquinoline framework.

Full text of DOI:10.1021/ol0359214

ORGANIC
LETTERS
2003
Vol. 5, No. 24
4733-4736
Anti-Markovnikov Intermolecular
Hydroamination: A Bis(amidate)
Titanium Precatalyst for the Preparation
of Reactive Aldimines
Zhe Zhang and Laurel L. Schafer*
The Department of Chemistry, The UniVersity of British Columbia, 2036 Main Mall,
VancouVer, BC, Canada V6T 1Z1
schafer@chem.ubc.ca
Received September 30, 2003
ABSTRACT
A bulky bis(N-2′,6′-diisopropylphenyl(phenyl)-amidate)titanium-bis(diethylamido) complex was identified as a highly active and regioselective
precatalyst for the anti-Markovnikov hydroamination of a wide range of terminal alkyl alkynes with alkylamines. This titanium complex was
fully characterized, including its X-ray crystal structure. The reactive aldimine products generated have been further elaborated using one-pot
procedures to give substituted amines, aldehydes, and the isoquinoline framework.
The catalytic addition of N-H across a carbon-carbon
multiple bond is a synthetically important transformation for
the preparation of amines and imines. Imines are versatile
building blocks for organic synthesis, as they are used to
prepare substituted amines and can function as masked
carbonyl substituents. The hydroamination of alkynes results
in the direct formation of imines with no side products. While
the development of catalytic methods for the hydroamination
of internal alkynes has been intensely investigated,1 the
regioselective hydroamination of terminal alkynes remains
an important synthetic challenge.2 In particular, selective anti-
Markovnikov hydroamination of terminal alkynes to give
aldimine products is an attractive synthetic target, as ald-
imines are useful reactive intermediates that can undergo
further synthetic elaboration.3 The only previous report of
highly anti-Markovnikov selective hydroamination of alkynes
was limited to the use of bulky tert-butylamine as a
substrate.2a Here we describe the development of a new bis-
(amidate)titanium precatalyst that displays high activity and
regioselectivity for the anti-Markovnikov hydroamination of
terminal alkyl alkynes with a wide range of alkylamines.
Furthermore, this easily prepared catalyst is tolerant of a wide
range of functional groups, making it generally applicable
for the synthesis of complex nitrogen-containing products.
Cyclopentadienyl complexes of Ti and Zr have been
shown to effectively catalyze the intermolecular hydroami-
nation of alkynes with primary amines.4 However, the
development of a flexible catalyst system that takes advan-
(1) For recent reviews see: (a) Muller, T. E.; Beller, M. Chem. ReV.
1998, 98, 675. (b) Novis, M.; Driessen-Ho¨lscher, B. Angew. Chem., Int.
Ed. 2001, 40, 3983. (c) Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M.
AdV. Synth. Catal. 2002, 344, 795. (d) Pohlki, F.; Doye, S. Chem. Soc.
ReV. 2003, 32, 104. (e) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003,
935. (f) Roesky, P. W.; Muller, T. E. Angew. Chem., Int. Ed. 2003, 42,
2708.
(2) (a) Tillack, A.; Castro, I. G.; Hartung, C. G.; Beller, M. Angew.
Chem., Int. Ed. 2002, 41, 2541. (b) Bytschkov, I.; Doye, S. Eur. J. Org.
Chem. 2001, 4411. (c) Cao, C.; Ciszewski, J. T.; Odom, A. T. Organome-
tallics 2001, 20, 5011. (d) Haskel, T.; Neyroud, T. G.; Kapon, M.;
Botoshansky, M.; Eisen, M. S. Organometallics 2001, 20, 5017.
(3) Castro, C. G.; Tillack, A.; Hartung, C. G.; Beller, M. Tetrahedron
Lett. 2003, 44, 3217 and references therein.
10.1021/ol0359214 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/22/2003

Table 1. Intermolecular Hydroamination with Tunable Bis(amidate)titanium-Bis(amido) Precatalysts
t
% yield
entry
R
(h)
(anti-Markovnikov/Markovnikov)a
1
2
3
4
5
iPr
tBu
Ph
24
24
24
10
6
no reaction
71 (5:1)
55 (99:1)
78 (>99:1)
82 (>99:1)
2,6-dimethylphenyl
2,6-diisopropylphenyl
1
a Yields were determined by H NMR with an internal standard (1,3,5-trimethoxybenzene). Ratio confirmed by GCMS after hydrolysis.
tage of the low cost and high reactivity of the group 4 metals
while providing enhanced and selective reactivity remains
an area of intense investigation.5 Inspired by the work of
Beller and co-workers, who reported titanium-catalyzed anti-
Markovnikov hydroamination with bulky amine substrates,2a
we sought to develop a flexible catalyst system based on
readily available amidate ligands to afford easily prepared
complexes with broadly applicable reactivity.
anhydrous ether, followed by removal of all volatiles to give
a red microcrystalline solid (eq 1). These crude materials
were used in a preliminary screen to identify the most active
precatalyst for the hydroamination of 1-hexyne with tert-
butylamine (Table 1). These reactions were carried out on
NMR tube scale at 65 °C for up to 24 h. The reaction
progress was monitored by 1H NMR spectroscopy by
observing the disappearance of the terminal alkyne proton
at 2.1 ppm and the appearance of the diagnostic signals for
the aldimine anti-Markovnikov product (triplet at 7.5 ppm)
and the ketimine Markovnikov product (singlet at 1.9 ppm).
As shown in Table 1, the easily modified amide proligand
permits the preparation of complexes displaying tunable
relative reactivity. The bulkiest substituent is the most
effective, with the 2,6-diisopropylphenyl derivative (entry
5, complex 1) resulting in the highest yields and lowest
reaction times. Most importantly, the most active precatalyst
was also highly regioselective with only the anti-
Markovnikov product being observed.
Complex 1 was recrystallized from benzene and was fully
characterized, including X-ray crystallographic analysis
(Figure 1). The bis(amidate)titanium complex is C2 sym-
metric, with the N atoms of the amidate ligands being trans
to each other, while the amide ligands are in a cis orientation.
The crystalline precatalyst has catalytic behavior identical
to that of the bulk material; thus, the easily isolated crude
product was used for all catalytic investigations.
Organic amides are attractive proligands, as they have an
easily modified structure that allows for variable steric and
electronic properties in the resultant complexes. Surprisingly,
amidates have been rarely employed as auxiliary ligands in
transition metal chemistry.6 We are investigating this easily
varied N,O chelating ligand as a flexible scaffold for the
preparation of highly selective and reactive catalysts. Previ-
ously we reported that varying the electronic properties of
the amidate ligand while maintaining consistent steric
properties could dramatically modify reactivity.7 However,
these preliminary catalyst systems had limited substrate
tolerance. Here we probe the effect of the steric environment
about the reactive metal center by changing the substituents
on the N of the amidate ligand. In particular, the catalyst
identified gives unprecedented anti-Markovnikov selectivity
for a wide range of substrates with various steric properties
and functional groups. The reactive aldimine products
generated have been further elaborated using one-pot pro-
cedures to give substituted amines, aldehydes, and a more
complex structural motif, the isoquinoline framework.
Consistent with previously reported mechanistic investiga-
tions for titanium catalyzed hydroamination,9 we propose
titanium-imido species as the catalytically active complexes.
This is supported by the observation that the bis(amidate)
(5) (a) Ackermann, L.; Bergman, R. G.; Loy, R. N. J. Am. Chem. Soc.
2003, 125, 11956. (b) Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom,
A. L. Chem. Commun. 2003, 586. (c) Ong, T.-G.; Yap, G. A. P.; Richeson,
D. S. Organometallics 2002, 21, 2839.
(6) Giesbrecht, G. R.; Shafir, A.; Arnold, J. Inorg. Chem. 2001, 40, 6069.
(7) Li, C.; Thomson, R. K.; Gillon, B.; Patrick, B. O.; Schafer, L. L.
Chem. Commun. 2003, 2562.
The precatalysts described here were prepared by the
reaction of 2 equiv of amide with 1 equiv of Ti(NEt2)4 in
(8) See Supporting Information for relevant bond lengths and angles.
(9) (a) Johnson, J. S.; Bergman, R. G. J. Am. Chem. Soc. 2001, 123,
2923. (b) Pohlki, F.; Doye, S. Angew. Chem., Int. Ed. 2001, 40, 2305. (c)
Fairfax, D.; Stein, M.; Livinghouse, T.; Jensen, M. Organometallics 1997,
16, 1523.
(4) (a) Walsh, P. J.; Baranger, A.; Bergman, R. G. J. Am. Chem. Soc.
1992, 114, 1708. (b) Haak, E.; Bytschkov, I.; Doye, S. Angew. Chem., Int.
Ed. 1999, 38, 3389. (c) Pohlki, F.; Heutling, A.; Bytschkov, I.; Hotopp, T.;
Doye, S. Synlett 2002, 799.
4734
Org. Lett., Vol. 5, No. 24, 2003

in contrast to the previous report of anti-Markovnikov-
selective titanium catalysts, which require bulky tert-butyl-
amine to induce selectivity.2a Complex 1 can also tolerate
more sterically demanding substrates such as cyclohexyl- and
t-butylalkynes (entries 4-8); however, these reactions do
require prolonged reaction times.
To further test this catalyst system, the compatibility of
various functional groups with these reaction conditions was
investigated (Table 3). Reactions with alkynes containing
Table 3. Intermolecular Hydroamination of Functionalized
Terminal Alkynes to Give Imines that Can Be Hydrolyzed to
Carbonyl Derivatives
Figure 1. ORTEP plot of the structure of bis(amidate)titanium-
bis(amido) complex 1 at 50% ellipsoids.8
precatalyst is effective with a variety of primary amines as
substrates while secondary amines resulted in no detectable
hydroamination products.10
To probe the scope of catalysis, a selection of alkynes and
amines with differing steric bulk were screened (Table 2).
Table 2. Hydroamination of Terminal Alkynes with Various
Amines
a Isolated yield of hydrolysis products. b NMR yield of imine product
using 1,3,5-trimethoxybenzene as internal standard.
protected alcohols were carried out on small scale, and the
yields were determined for the resulting carbonyl-containing
hydrolysis products. Although reactions with protected
propargyl alcohol led to catalyst decomposition, productive
and selective reactivity was observed when the carbon chain
was extended by one or two carbons (entries 1-4). Interest-
ingly, propargylic amine, protected as the imine, was a
reactive substrate as observed by NMR spectroscopy. This
shows that protected primary amines can be incorporated at
even the most challenging positions within the substrate
(entries 5, 6). Also, in contrast to previously reported results
for titanium catalysts,2b precatalyst 1 can affect the hy-
droamination of trimethylsilylacetylene, with excellent yields
being obtained within 24 h (entries 7, 8). Furthermore, as
observed by 1H NMR spectroscopy, there were no diagnostic
signals in the olefinic region for the N-silylated eneamine
product, as has been observed with lanthanide- and actinide-
mediated hydroamination of silylated acetylenes.2d,11
a Isolated yields. 1H NMR spectroscopy used to determine ratios of
regioisomers. b Yields determined by 1H NMR spectroscopy with 1,3,5-
trimethoxybenzene as an internal standard.
In this case, the reaction was carried out on small scale with
benzene as a solvent. The resulting imine mixture was diluted
with ether and reduced with LAH to give the corresponding
amine products. With complex 1, we observe only the anti-
Markovnikov product with isopropylamine (entry 2) and even
the least sterically demanding substrate combination, benzyl-
amine with 1-hexyne (entry 3), resulted in the isolation of
the amine due to anti-Markovnikov hydroamination. This is
The results summarized in Tables 2 and 3 demonstrate
consistent regioselective hydroamination for a range of
(10) Not detected by NMR spectroscopy or GCMS.
(11) Li, Y.; Marks, T. J. Organometallics 1996, 15, 3770.
Org. Lett., Vol. 5, No. 24, 2003
4735

In summary, five bis(amidate)titanium-bis(amido) com-
plexes were screened and it was shown that the bulky bis-
(amidate) complex 1 is an effective precatalyst for anti-
Markovnikov regioselective, intermolecular hydroamination
of terminal alkyl alkynes with alkylamines. With this
precatalyst, secondary, tertiary, and quaternary alkyl-
substituted primary amines can be coupled with a range of
terminal alkynes to give exclusively the anti-Markovnikov
aldimine product. These reactive aldimine products can be
further elaborated to amines, aldehydes, or the isoquinoline
framework using efficient one-pot procedures. Mechanistic
investigations and further elaboration of the amidate ligand
to vary reactivity and selectivity in both intra- and inter-
molecular hydroamination of C-C multiple bonds are
ongoing, and results will be reported in due course.
Scheme 1. One-Pot Preparation of the Isoquinoline
Framework
substrates with variable steric bulk and functional group
incorporation. Consequently, precatalyst 1 was identified as
a suitable candidate for application in the synthesis of more
complex target molecules. Here, a novel hydroamination
route for the total synthesis of isoquinolines is achieved by
using a modified Pictet-Spengler reaction (Scheme 1).12 This
one-pot synthesis of the isoquinoline framework avoids the
use of a carbonyl-containing substrate and instead regio-
selective hydroamination with amine 4 gives the reactive
aldimine intermediate 5. Subsequent acid-catalyzed cycliza-
tion results in the formation of the corresponding isoquinoline
product 6 in 95% yield as a colorless oil.13
Acknowledgment. The authors thank the Natural Sci-
ences and Engineering Research Council of Canada (NSERC)
and UBC for financial support.
Supporting Information Available: Crystallographic
data for 1 (CIF) and experimental procedures and charac-
terization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(12) (a) Menachery, M. D.; Lavanier, G. L.; Wetherly, M. L.; Guinau-
deau, H.; Shamma, M. J. Nat. Prod. 1986, 49, 745. (b) Cox, E. D.; Cook,
J. M. Chem. ReV. 1995, 95, 1797.
(13) Gremmen, C.; Wanner, M. J.; Koomen, G.-J. Tetrahedron Lett. 2001,
42, 8885.
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