The Cp2TiMe2-catalyzed intramolecular hydroamination/cyclization of aminoalkynes

Article abstract of DOI:10.1016/S0040-4039(02)00644-5

Cp₂TiMe₂ has been found to be a competent catalyst for the intramolecular hydroamination/cyclization of aminoalkynes. In the presence of 5.0 mol% Cp₂TiMe₂, the hydroamination reactions proceed smoothly at 100-110°C to give five- and six-membered cyclic imines within 4-6 h. After subsequent reduction performed with zinc-modified NaBH₃CN at room temperature cyclic amines can be isolated in good yields.

Full text of DOI:10.1016/S0040-4039(02)00644-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3715–3718
The Cp2TiMe2-catalyzed intramolecular
hydroamination/cyclization of aminoalkynes
Igor Bytschkov and Sven Doye*
Institut fu¨r Organische Chemie, Universita¨t Hannover, Schneiderberg 1B, D-30167 Hannover, Germany
Received 22 February 2002; accepted 22 March 2002
Abstract—Cp2TiMe2 has been found to be a competent catalyst for the intramolecular hydroamination/cyclization of aminoalky-
nes. In the presence of 5.0 mol% Cp2TiMe2, the hydroamination reactions proceed smoothly at 100–110°C to give five- and
six-membered cyclic imines within 4–6 h. After subsequent reduction performed with zinc-modified NaBH3CN at room
temperature cyclic amines can be isolated in good yields. © 2002 Elsevier Science Ltd. All rights reserved.
The addition of ammonia or primary and secondary
amines to alkenes and alkynes offers a very interesting
pathway to amines, imines and enamines by converting
inexpensive alkenes and alkynes into the desired prod-
ucts in a single reaction without any formation of side
products. However, efforts to develop efficient
hydroamination protocols have met with only limited
success,1 except by using early transition metal com-
plexes as catalysts for the hydroamination of alkynes.2
In 1992 Bergman et al. reported that Cp2Zr(NH-2,6-
Me2C6H3)2 catalyzes the hydroamination of various
alkynes with 2,6-dimethylaniline,2a,2b and Livinghouse
et al. demonstrated that CpTiCl3 and CpTiMe2Cl can
be used as catalysts for the intramolecular hydroamina-
tion of aminoalkynes.2d–g However, intermolecular
hydroaminations using these catalysts were not success-
ful. Since 1999 several reports from our group have
dealt with applications of the well known reagent
intramolecular hydroamination and subsequent
reduction.4
Inspired by
a
mechanistic investigation of the
Cp2TiMe2-catalyzed intermolecular hydroamination of
alkynes, which suggested that the rate of related
hydroamination reactions can be increased by an accel-
erated [2+2]-cycloaddition between the catalytically
active titanium imido complex and the alkyne,2j we
focused
on
intramolecular
Cp2TiMe2-catalyzed
hydroamination/cyclization reactions of aminoalkynes
(Scheme 1) because in this case the mentioned [2+2]-
cycloaddition is supposed to be fast.
As substrates we used the aminoalkynes 1–11 (Table 1),
which are easily accessible from commercially available
starting materials by standard transformations.5 Ini-
1
tially performed H NMR experiments employing the
Cp2TiMe2 as hydroamination catalyst.2h–m While this
g-aminoalkynes 1 and 2 showed that intramolecular
hydroamination/cyclization reactions in the presence of
5.0 mol% Cp2TiMe2 are in fact fast at 100°C in C6D6.
After only 4 h, 1 and 2 were completely consumed and
transformed into the corresponding cyclic imines in
3
catalyst has been used extensively for intermolecular
hydroamination reactions of alkynes, it has not been
reported that Cp2TiMe2 can also be used for the syn-
thesis of cyclic amines from aminoalkynes by catalytic
.
R
NaBH3CN, ZnCl2 Et2O
5.0 mol % Cp2TiMe2
n
n
R
R
n
toluene, 110°C, 6 h
H2N
N
N
H
THF, 25°C, 20 h
n = 1, 2
Scheme 1. One-pot synthesis of cyclic amines from aminoalkynes by Cp2TiMe2-catalyzed intramolecular hydroamination and
subsequent reduction.
Keywords: alkynes; amination; amines; catalysis; titanium.
* Corresponding author. Fax: +49 (0)511 762 3011; e-mail: sven.doye@oci.uni-hannover.de
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00644-5

3716
I. Bytschko6, S. Doye / Tetrahedron Letters 43 (2002) 3715–3718
Table 1. One-pot synthesis of cyclic amines from aminoalkynes by Cp2TiMe2-catalyzed intramolecular hydroamination and
subsequent reduction
a
Reaction conditions: (1) aminoalkyne (1.0 mmol), Cp2TiMe2 (0.05 mmol, 5.0 mol%), toluene (0.5 mL), 110°C, 6 h; (2) NaBH3CN (2.0 mmol),
ZnCl2·Et2O (1.0 mmol), THF (5.0 mL), 25°C, 20 h. Yields represent isolated yields of pure compounds as determined by 1H and 13C NMR as
well as GC or TLC analysis.
b The scale of the reaction was 8.0 mmol. No additional toluene was added to the reaction mixture. The product was isolated by Kugelrohr
distillation.

I. Bytschko6, S. Doye / Tetrahedron Letters 43 (2002) 3715–3718
3717
almost quantitative yield (98%, internal standard
Cp2Fe). In both cases no formation of any side prod-
ucts was observed. These results clearly indicate that in
contrast to intermolecular reactions reported in the
past2h–k Cp2TiMe2-catalyzed intramolecular hydroami-
nation reactions do not require a sterically demanding
amine part of the aminoalkyne to take place efficiently.
With these promising results in hand, we focused on a
one-pot hydroamination/reduction sequence for the
synthesis of cyclic amine derivatives on a preparative
scale. For that purpose, we cyclized 1–11 in the pres-
ence of 5.0 mol% Cp2TiMe2 in toluene at 110°C. After
a reaction time of 6 h a subsequent reduction per-
formed with zinc-modified NaBH3CN6,7 in THF at
room temperature gave access to the desired cyclic
amines 12–22 which were isolated in pure form after
chromatography on silica gel (Scheme 1, Table 1).8,9
does not offer significant advantages over other cata-
lysts. However, since it is well established that this
Ti-compound also catalyzes intermolecular hydroami-
nation reactions of alkynes2h–m the present study
undoubtedly proves that Cp2TiMe2 must be recognized
as the most general catalyst for the hydroamination of
alkynes known today. Furthermore, it is extremely
interesting that in contrast to intermolecular reactions,
Cp2TiMe2-catalyzed intramolecular hydroamination
reactions do not require a sterically demanding amine
part of the aminoalkyne to take place efficiently. This
result strongly supports our interpretations of a mecha-
nistic study of the Cp2TiMe2-catalyzed intermolecular
hydroamination of alkynes.2j However, in combination
with an imine reduction, the intramolecular hydroami-
nation reactions can be used for a convenient one-pot
synthesis of cyclic amines from aminoalkynes.
The examples shown in Table 1 demonstrate, that
under the employed reaction conditions g- and d-
aminoalkynes can be converted smoothly into five- and
six-membered cyclic amine derivatives. Due to the
mechanism of the reaction the hydroamination step
takes place without any formation of regioisomeric
products. An aromatic ring adjacent to the alkyne can
be electron neutral (entries 1, 8, 11), electron rich (entry
2) or electron deficient (entries 4, 5, 10) as well as ortho
substituted (entries 3, 4, 9, 10). However, as can be seen
from entries 6 and 7 an aromatic ring adjacent to the
alkyne is not required for the hydroamination reaction
to proceed. Interestingly, aromatic halide and methoxy
substituents, which offer the possibility of further trans-
formations, are tolerated under the reaction conditions.
With one exception, the yields are good to excellent for
both the synthesis of pyrrolidine and piperidine deriva-
tives. Only in the case of 6 (entry 6), the product 17 was
isolated in a modest yield. However, the reason for this
might be the low boiling point of 17 and the fact that
17 was isolated by Kugelrohr distillation and not by
chromatography. In contrast to the mentioned results,
the one-pot synthesis of seven- and eight-membered
Acknowledgements
Generous support by Professor E. Winterfeldt is most
gratefully acknowledged. We also thank the Deutsche
Forschungsgemeinschaft, the Fonds der Chemischen
Industrie and Bayer AG for financial support of our
research.
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1
cyclic amines could not be achieved. Related H NMR
experiments performed with corresponding aminoalky-
nes in C6D6 at 100°C proved that the hydroamination/
cyclization reactions are very slow in these cases (yields
<30% after 3 days). Since intermolecular hydroamina-
tion reactions of sterically less demanding n-alkyl-
amines are extremely slow in the presence of
2h–n
Cp2TiMe2
no efforts have been made to expand the
Cp2TiMe2-catalyzed intramolecular hydroamination to
larger rings. Finally, we tried to minimize the amount
of the hydroamination catalyst. However, during a
cyclization of aminoalkyne 8 performed in the presence
of 2.0 mol% Cp2TiMe2 at 110°C in C6D6 (sealed
Schlenk tube) the corresponding imine was only formed
in 29% yield after 4 h.
In summary, the results presented clearly indicate that
Cp2TiMe2 is an active catalyst for the intramolecular
hydroamination/cyclization of aminoalkynes. Unfortu-
nately, the employed reaction conditions are relatively
harsh compared to most other catalytic procedures for
intramolecular hydroaminations.4 Therefore, Cp2TiMe2

3718
I. Bytschko6, S. Doye / Tetrahedron Letters 43 (2002) 3715–3718
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and concentrated under vacuum. Purification by flash
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afforded the pure cyclic amine derivative.
1
9. Representative characterization data for 13: H NMR (400
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and references cited therein.
5. Gagne´, M. R.; Stern, C. L.; Marks, T. J. J. Am. Chem.
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MHz, CDCl3): l=7.12 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.6
Hz, 2H), 3.77 (s, 3H), 3.12–3.22 (m, 1H), 2.98–3.05 (m,
1H), 2.76–2.85 (m, 1H), 2.64–2.74 (m, 2H), 2.23 (br. s,
1H), 1.64–1.87 (m, 3H), 1.31–1.42 (m, 1H) ppm; 13C NMR
(100.6 MHz, DEPT, CDCl3): l=157.9 (C), 132.1 (C),
129.8 (CH), 113.7 (CH), 60.5 (CH), 55.1 (CH3), 46.0
(CH2), 41.2 (CH2), 31.0 (CH2), 24.7 (CH2) ppm; IR:
w=3272, 2956, 2873, 1608, 1539, 1512, 1493, 1453, 1402,
1362, 1311, 1246, 1173, 1152, 1109, 1059, 1034, 957, 906,
811, 767, 740 cm−1; MS (25°C): m/z (%)=191 (24) [M+],
190 (11) [M+−1], 174 (13), 162 (6), 147 (9), 134 (7), 121
(40), 112 (14), 91 (24), 89 (9), 78 (27), 71 (34), 70 (100), 68
6. Kim, S.; Oh, C. H.; Ko, J. S.; Ahn, K. H.; Kim, Y. J. J.
Org. Chem. 1985, 50, 1927–1932.
7. Other reducing agents (H2, Pd/C, LiAlH4, DIBAH, etc.)
can be used as well. However, best results were obtained
with NaBH3CN in the presence of ZnCl2·Et2O.
8. General procedure: Under an inert atmosphere of argon, a
flame-dried Schlenk tube equipped with a Teflon stopcock
1
(28), 65 (12); purity by GC: 99%. 21: H NMR (400 MHz,
and
a magnetic stirring bar was charged with the
CDCl3): l=8.90–10.20 (br. s, 1H), 7.60 (s, 1H), 7.42–7.52
(m, 2H), 3.70 (d, J=9.2 Hz, 1H), 3.58 (d, J=12.9 Hz, 1H),
3.28–3.38 (m, 2H), 2.95 (t, J=12.8 Hz, 1H), 1.96–2.12 (m,
1H), 1.76–1.96 (m, 3H), 1.66 (d, J=13.7 Hz, 1H), 1.31–
1.42 (m, 1H) ppm; 13C NMR (100.6 MHz, DEPT, CDCl3):
l=138.2 (C), 134.8 (C), 130.3 (CH), 129.5 (C, q, J=33
Hz), 128.7 (CH, q, J=3.5 Hz), 125.6 (CH, q, J=3.8 Hz),
123.4 (C, q, J=272 Hz), 56.3 (CH), 44.8 (CH2), 36.9
(CH2), 27.3 (CH2), 22.2 (CH2), 21.9 (CH2) ppm; IR:
w=3117, 3044, 2955, 2929, 2817, 2791, 2762, 2714, 2678,
2559, 2500, 2449, 2360, 2323, 2051, 1983, 1712, 1613, 1587,
1468, 1443, 1415, 1385, 1332, 1275, 1200, 1176, 1122, 1078,
1030, 990, 959, 933, 895, 828, 752, 729, 656, 600, 566, 533,
517 cm−1; MS (60°C): m/z (%)=277 (1) [M+], 240 (3), 222
(12), 193 (11), 159 (6), 158 (4), 145 (2), 98 (2), 85 (17), 84
(100), 70 (2), 67 (3); purity by GC: 99%.
aminoalkyne (1.0 mmol), Cp2TiMe2 (0.20 mL, c=0.25
mol/L in toluene, 0.05 mmol, 5.0 mol%) and toluene (0.3
mL). The resulting mixture was heated to 110°C for 6 h.
After the mixture had been cooled to room temperature,
the solvent was removed under vacuum and a suspension
of NaBH3CN (126 mg, 2.0 mmol) and ZnCl2·Et2O (1.0
mL, c=1.0 mol/L in Et2O, 1.0 mmol) in THF (5.0 mL)
was added. The resulting mixture was stirred for 20 h at
room temperature. After the mixture had been diluted
with CH2Cl2 (10.0 mL) and aqueous HCl (10.0 mL, c=2.0
mol/L), stirring at room temperature was continued for
additional 2 h. Then the resulting layers were separated
and KOH (c=2.0 mol/L) was added to the aqueous layer
until pH 7 was reached. The aqueous layer was extracted
with CH2Cl2 (3×50 mL). The combined organic layers
were extracted with water and brine, dried with Na2SO4