Organolanthanide catalyzed intramolecular 5-endo-dig hydroamination: An unusual anti-Markovnikov cyclization

Article abstract of DOI:10.3987/COM-04-S(P)10

Intramolecular 5-endo-dig hydroaminations of homopropargylamine derivatives were efficiently catalyzed by the organolanthanide precatalyst, Cp*₂YbCH(TMS)₂ (Cp* = C₅Me₅), to give the endocyclic enamine products. The 5-endo-dig hydroamination was also preferred in the presence of another olefin that would afford a 6-exo cyclization.

Full text of DOI:10.3987/COM-04-S(P)10

HETEROCYCLES, Vol. 64, 2004
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HETEROCYCLES, Vol. 64, 2004, pp. 467 - 474
Received, 6th May, 2004, Accepted, 22nd July, 2004, Published online, 30th July, 2004
ORGANOLANTHANIDE CATALYZED INTRAMOLECULAR
5-ENDO-DIG HYDROAMINATION: AN UNUSUAL ANTI-
MARKOVNIKOV CYCLIZATION†
Gary A. Molander* and Hikaru Hasegawa
Roy and Diana Vagelos Laboratory, Department of Chemistry, University of
Pennsylvania, 231 South 34th Street, Philadelphia, PA, USA, 19104-6323,
gmolandr@sas.upenn.edu
Abstract – Intramolecular 5-endo-dig hydroaminations of homopropargylamine
derivatives were efficiently catalyzed by the organolanthanide precatalyst,
Cp*2YbCH(TMS)2 (Cp* = C5Me5), to give the endocyclic enamine products.
The 5-endo-dig hydroamination was also preferred in the presence of another
olefin that would afford a 6-exo cyclization.
INTRODUCTION
Carbon-nitrogen bond-forming reactions between unsaturated carbon-carbon bonds and amines represents
one of the more challenging current themes in organic synthesis. Because both amines, and alkenes and
alkynes, are electron rich, activation of the C-C multiple bond or the nitrogen center of an amine is
necessary to induce such a coupling. Recently, organolanthanide-catalyzed hydroaminations have been
developed as an attractive means to form C-N bonds.1 The reaction has been principally used for
intramolecular hydroamination with aminoalkynes,2 aminoalkenes3 and aminoallenes4 to synthesize
nitrogen containing heterocycles. Some applications of this method to natural product synthesis have also
been reported.5, 6
In our laboratory, an asymmetric synthesis of the monocyclic alkaloid pinidinol using an organolanthanide
catalyzed intramolecular hydroamination was accomplished and reported recently.6
†Dedicated with great respect and admiration to Dr. Pierre Potier on his 70th birthday.

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During the course of our investigations into the use of organolanthanide catalysts for polycyclic alkaloid
synthesis,7 a unique anti-Markovnikov intramolecular 5-endo-dig hydroamination was discovered
(Scheme 1). Thus, the reaction of homopropargylamine substrate (1) using an organolanthanide catalyst
afforded not the desired 6-exo, 6-exo tandem cyclic product (2), but rather led to 5-endo ring closure
product (3) via an intramolecular anti-Markovnikov addition to the alkyne. Although there are examples
of organolanthanide catalyzed hydroamination of aminoalkynes,1,2 to the best of our knowledge this is the
first example of a 5-endo-dig hydroamination. Herein we wish to report our preliminary studies of this
unusual reaction.
Scheme 1
Ln cat.
Ln cat.
> 95%
N
HN
N
X
3
1
2
RESULTS AND DISCUSSION
At the outset of our studies, several organolanthanide catalysts were tested for the intramolecular
5-endo-dig hydroamination, and a simple N-benzylhomopropargylamine (4)8 was chosen as the amine
substrate to optimize the reaction conditions. Ansa-bridged precatalyst Me2SiCp"2NdCH(TMS)2 (Cp" =
C5Me4), often employed as a good precatalyst for intramolecular hydroaminations,9 was tested (Table 1).
Thus, a solution of the homopropargylamine (4) (10 µmol) in C6D6 (0.02 M) was added to a sealable
1
NMR tube in which was placed 1 µmol of the precatalyst. The reaction was monitored by H NMR
spectroscopy. However, this reaction did not proceed and only starting material was recovered (entry 1).
Similar reactions using Cp*2NdCH(TMS)2 and Cp*2SmCH(TMS)2 gave many products, with a small
amount of the 5-endo ring closure product (5) being detected in the latter case (entries 2 and 3). The
Cp*2YbCH(TMS)2 precatalyst, having a smaller ionic radius, was next utilized in conjunction with
substrate (4). We were pleased to find that 5-endo hydroamination took place to give the desired enamine
product (5) quantitatively (entry 4).10 Other types of organolanthanide precatalysts (Cp*2YMe•THF and
Cp*2LuMe•THF) were also employed under the same reaction conditions, although they were determined
to be less efficient (entries 5 and 6). From these observations it was determined that organolanthanide
catalysts possessing metals with a small ionic radius were more efficient for the 5-endo hydroamination of
the homopropargylamine substrate, even though increasing the lanthanide ionic radius (Lu < Yb < Y < Sm
< Nd)11 and opening the metal coordination sphere, such as with the ansa-bridged precatalyst

HETEROCYCLES, Vol. 64, 2004
469
Me2SiCp"NdCH(TMS)2, usually gave higher reactivity in intramolecular9 as well as in intermolecular
hydroaminations.12
a
Table 1. Screening of organolanthanide precatalysts for intramolecular 5-endo-dig hydroamination
Ln catalyst (10 mol%)
N
NH
C6D6 (0.02 M), 20 °C
Ph
Ph
4
5
b
b
entry
Yield%
Ln cat.
Time Conv.%
c
1
2
3
4
5
6
-
Me2SiCp"2NdCH(TMS)2
Cp*2NdCH(TMS)2
Cp*2SmCH(TMS)2
Cp*2YbCH(TMS)2
Cp*2YMe•THF
3 d
3 d
3 d
1 d
2 d
9 d
N.R.
70
d
0
e
20
70
>95
>95
60
f
30
f
40
Cp*2LuMe•THF
90
a
b
c
d
e
f
The reaction was carried out in an NMR tube with 10 mol% of lanthanide catalyst.
Conversion and yield were determined by 1H NMR spectroscopy.
No reaction. Only starting amine was recovered.
Complex mixture.
Other products were found by 1H NMR spectroscopy.
There were two other products.
The reaction conditions for the intramolecular 5-endo hydroamination were optimized using
Cp*2YbCH(TMS)2 (Table 2). The 5-endo hydroaminations of homopropargylamine (4) were carried out
1
under several concentrations in C6D6 using 5 mol% of Yb precatalyst and were monitored by H NMR.
Increasing the concentration afforded faster reactions as is usual in hydroaminations (entries 1 to 4),9
although some byproducts were generated under the higher concentration reaction conditions (entry 4).
Competitive product inhibition,13 which causes a decrease of the reaction rate, was noticed during the
monitoring of these reactions. Indeed, this effect led to incomplete reaction when less Yb precatalyst was
used (entries 5 and 6). Fortunately, a higher reaction temperature solved this problem and allowed the use
of 3 mol% of Yb precatalyst to achieve satisfactory results (entry 7).
Unfortunately, all efforts to isolate the endocyclic enamine product (5) failed due to the instability of the
product. However, enamine (5) was reduced to give the stable product, N-benzylpyrrolidine (6), according
to the reported procedure (eq. 1).14 Thus, after completion of the 5-endo hydroamination of
homopropargylamine (4), the reaction solution was poured into a MeOH solution containing NaBH3CN (5
equiv.) and ZnCl2 (2.5 equiv.). After stirring for 1 h and the proper workup, column purification of the

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HETEROCYCLES, Vol. 64, 2004
crude sample by basic Al2O3 gave N-benzylpyrrolidine (6), which was identified by comparison of its 1H
NMR and MS with an authentic sample.15
a
Table 2. Optimization of reaction conditions for intramolecular 5-endo-dig hydroaminations
Cp* YbCH(TMS)2
2
NH
N
C6D6
Ph
Ph
4
5
b
c
d
d
entry
Temp.
Conc.
mol%
Time Conv.%
Yield%
1
2
3
4
5
6
7
8
20 °C
20 °C
20 °C
20 °C
20 °C
20 °C
60 °C
60 °C
0.02
0.05
0.1
5
5
5
5
3
1
3
1
2 d
2 d
1 d
12 h
1 d
3 d
>95
>95
>95
>95
80
>95
>95
90
e
0.2
85
e
0.1
80
e
0.1
50
80
0.1
<1 h 90
6 h
90
95
e
0.1
90
a
b
c
d
e
The reaction was carried out in an NMR tube.
Concentration (mol/L) of the starting amine in C6D6.
Amount of lanthanide catalyst.
Conversion and yield were determined by 1H NMR spectroscopy.
Byproducts were found by 1H NMR spectroscopy.
The low isolated yield was caused not from the hydroamination but from generation of a byproduct under
the reducing conditions. Thus, the dimerized product obtained from the enamine product and its iminium
ion intermediate is generated in substantial quantities under these reaction conditions.16
1) Cp* YbCH(TMS)2
2
2) NaBH3CN, ZnCl2
(1)
NH
Ph
N
55%
Ph
4
6
Surprisingly, the 5-endo hydroamination product was formed in preference to the 6-exo hydroamination
product (Scheme 2). Thus, the hydroamination of amine (1) under the optimized conditions (Table 2,
entry 7) took place to give only 5-endo ring closure product (3). The starting amine was consumed in 1 h
1
as determined by H NMR spectroscopy. To the best of our knowledge, this is the first example of a
5-endo-dig hydroamination taking place in the presence of a second olefin positioned for 6-exo cyclization,

HETEROCYCLES, Vol. 64, 2004
471
although there are many examples of 5-endo-dig cyclization catalyzed by transition metals.17 This
selectivity was also observed in the hydroamination of diyne substrates (7) and (8), even though the
carbon-carbon triple bond, especially the alkyne substituted by the trimethylsilyl group, has a higher
reactivity than a carbon-carbon double bond in organolanthanide catalyzed hydroaminations.2 Similar
selectivity was observed in the transformation of 11 to 12.
Scheme 2. Intramolecular 5-endo-dig hydroamination of amine derivatives having another olefin at the 6-exo position.
cat. Cp* YbCH(TMS)2
N
HN
2
C6D6, 60 °C
a
>95%
1
3
N
R
cat. Cp* YbCH(TMS)2
HN
2
C6D6, 60 °C
R
85%a
80%a
7; R = Ph
9; R = Ph
8; R = TMS
10; R = TMS
NH
N
10% Cp* YbCH(TMS)2
2
C6D6, 60 °C, 3 h
N
N
a
90%
Ph
Ph
11
Yields were determined by 1H NMR spectroscopy.
12
a
The mechanism of organolanthanide catalyzed hydroamination has been proposed to occur through a
four-centered transition structure involving insertion of a C-C multiple bond into the lanthanide-amide
bond.9,12,13 However, it is difficult to imagine this paradigm for the 5-endo hydroamination. In the hope of
shedding some light on the mechanism of the current transformation, deuterated homopropargylamines
were prepared and transformed with Cp*2YbCH(TMS)2 in reactions monitored by 1H NMR spectroscopy
(Scheme 3). Surprisingly, the 1H NMR spectrum of the hydroamination of nitrogen-deuterated amine (13)
showed two products (15) and (16). Integration of the 2- (δ = 5.87) and 3-position (δ = 4.75) enamine
protons indicated 0.5 H protons at each position, and each of these integrated to one-fourth the amount of
protons at the other methylene position (benzyl, 4- and 5-position, δ= 3.64, 2.34, 2.81 for 2H). A similar

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result was obtained from the hydroamination of the amine deuterated at the terminal alkyne (14).
Changing the reaction conditions (e.g., concentration and temperature) made no difference in the product
ratio. Although there is an example of deuterium scrambling in a hydroamination catalyzed by a rhodium
catalyst,18 the current labeling studies have unfortunately provided few details on the mechanism of the
reaction. As expected, the hydroamination of dideuterated amine (17) gave the dideuterated product (18).
Scheme 3. Hydroamination of deuterated amine substrates.
H
Ph
D
D
Y
Cp* YbCH(TMS)2
2
D
H
+
N X
Ph
N
N
C6D6
a
Ph
> 95%
15
16
13; X = D, Y = H
14; X = H, Y = D
50 : 50
D
Cp* YbCH(TMS)2
2
D
N D
Ph
N
C6D6
Ph
a
> 95%
17
18
a
Yields were determined by 1H NMR spectroscopy.
CONCLUSIONS
The first example of organolanthanide catalyzed intramolecular 5-endo-dig hydroamination had been
reported. It is noteworthy that Cp*2YbCH(TMS)2, having a relatively small ionic radius, is a suitable
catalyst for this reaction. More detailed experiments to determine the reaction mechanism and to apply the
enamine products as intermediates in organic synthesis are being conducted in our laboratory.
EXPERIMENTAL
General Procedure.
Preparation of homopropargylamine substrates for hydroamination.
N-3-Butynyl-(2-ethenylphenyl)methylamine (1): To the solution of 2-ethenylbenezeneacetonitrile in Et2O
(0.3 M) was slowly added a solution of diisobutylaluminum hydride in hexane (2.5 equiv.) under an argon
atmosphere at -78 °C. The reactant was allowed to warm to -40 °C and stirred for 3 h. The solution of
3-butynylamine hydrochloride (2.0 equiv.) in methanol (1.0 M) was then added into the reactant at –40 °C.
After stirring for 2 h at rt, the reactant was quenched with saturated NH4Cl aqueous solution. The
precipitate was removed through a Celite pad and the aqueous solution was extracted with Et2O. The ether
solution was dried over MgSO4 and concentrated in vacuo. Purification of the crude sample by SiO2

HETEROCYCLES, Vol. 64, 2004
473
column chromatography (10 : 1 EtOAc : i-PrOH as eluent) gave the title substrate. The amine substrate
was further purified by recrystallization of its HCl salt from EtOH/1,2-dichloroethane.
Preparation of homopropargylamine solution in C6D6: The homopropargylamine HCl salt, which was
prepared according to the above procedure or the known procedure for N-benzyl-3-butynylamine (4),8 was
neutralized with 2N NaOH in a small vial, and it was then extracted with C6D6 (ca. 2 mL) 3 times. The
amine solution in C6D6 was placed into a Schlenk flask and dried over MS 4Å. After degassing of the
solution, it was moved into a nitrogen-filled glove box and diluted with C6D6 to make the appropriately
concentrated amine solution.
General procedure for hydroaminations: A solution of the homopropargylamine (10 µmol) in C6D6
(0.02 M) was added to a sealable NMR tube in which was placed 1 µmol of the precatalyst. The reaction
was monitored by 1H NMR spectroscopy. The yield was also determined by 1H NMR spectroscopy.
Reduction of hydroamination product 5; Preparation of N-Benzylpyrrolidine (6)10: After completion
of the hydroamination of homopropargylamine (4), the reaction solution was poured quickly into a MeOH
solution containing NaBH3CN (5 equiv.) and ZnCl2 (2.5 equiv.). After stirring for 1 h, the reaction was
quenched with saturated NH4Cl aqueous solution, and it was then extracted with Et2O. Purification of the
crude sample by basic Al2O3 column chromatography (30 : 1 hexane EtOAc as eluent) gave
N-benzylpyrrolidine (6).
ACKNOWLEDGEMENTS
We gratefully acknowledge the National Institutes of Health (GM48580) for financial support. H.H. also
acknowledges Uehara Memorial Foundation for fellowship support.
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1
10. NMR spectral data of 5: H NMR (500 MHz, C6D6) δ 2.34 (2H, t, J = 9.0 Hz), 2.80 (2H, t, J = 9.0
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