Cp*2TiMe2: An improved catalyst for the intermolecular addition of n-alkyl- and benzylamines to alkynes

Article abstract of DOI:10.1021/jo016311p

Cp*₂TiMe₂ has been found to be a competent catalyst for the intermolecular addition of sterically less demanding n-alkyl- and benzylamines to internal alkynes. In the presence of 2.0-6.0 mol % of the catalyst, hydroamination reactions between n-propyl-, n-hexyl-, benzyl-, p-methoxybenzyl- or 2-phenylethylamine and diphenylacetylene, 3-hexyne or 4-octyne go to completion within 24 h or less at 114°C (oil bath temperature). After subsequent reduction of the initially formed imines with zinc-modified sodium cyanoborohydride in MeOH at 25°C, the corresponding secondary amines can be isolated in excellent yields (> 78%). Hydroamination/reduction sequences employing the unsymmetrically substituted alkyne 1-phenylpropyne give access to mixtures of regioisomeric secondary amines. The observed regioselectivity is low.

Full text of DOI:10.1021/jo016311p

J . Org. Chem. 2002, 67, 1961-1964
1961
Notes
Recently, we found that titanium complexes can be
used as catalysts for the intermolecular hydroamination
of alkynes. Among the investigated titanium compounds,
Cp *2TiMe2: An Im p r oved Ca ta lyst for th e
In ter m olecu la r Ad d ition of n -Alk yl- a n d
Ben zyla m in es to Alk yn es
Cp2TiMe2 was found to be the most efficient catalyst.7
6
With this catalyst, primary aryl- and alkylamines can
be coupled to symmetrically and unsymmetrically sub-
stituted alkynes. In the case of arylalkylalkynes, the
reaction occurs with high regioselectivity, forming the
anti-Markovnikov products exclusively. In contrast, reac-
tions employing terminal alkynes lead to regioisomeric
mixtures.8 While aniline derivatives and sterically hin-
dered sec- and tert-alkylamines react smoothly under the
reaction conditions (100-110 °C, toluene) a significant
Andreas Heutling and Sven Doye*
Institut fu¨r Organische Chemie, Universita¨t Hannover,
Schneiderberg 1B, D-30167 Hannover, Germany
sven.doye@oci.uni-hannover.de
Received November 23, 2001
Abstr a ct: Cp*2TiMe2 has been found to be a competent
catalyst for the intermolecular addition of sterically less
demanding n-alkyl- and benzylamines to internal alkynes.
In the presence of 2.0-6.0 mol % of the catalyst, hydroami-
nation reactions between n-propyl-, n-hexyl-, benzyl-, p-
methoxybenzyl- or 2-phenylethylamine and diphenylacetyl-
ene, 3-hexyne or 4-octyne go to completion within 24 h or
less at 114 °C (oil bath temperature). After subsequent
reduction of the initially formed imines with zinc-modified
sodium cyanoborohydride in MeOH at 25 °C, the corre-
sponding secondary amines can be isolated in excellent
yields (>78%). Hydroamination/reduction sequences employ-
ing the unsymmetrically substituted alkyne 1-phenylpro-
pyne give access to mixtures of regioisomeric secondary
amines. The observed regioselectivity is low.
(3) For intermolecular hydroaminations of alkenes, see: (a) Coulson,
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The addition of ammonia or primary and secondary
amines to nonactivated alkenes and alkynes is potentially
the most efficient approach toward the synthesis of
higher substituted nitrogen-containing products. It rep-
resents the most atom economic process for the formation
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However, at the moment only a few efficient hydroami-
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L. Angew. Chem., Int. Ed. Engl. 1975, 14, 369-370. (b) Hegedus, L. S.
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10.1021/jo016311p CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/28/2002

1962 J . Org. Chem., Vol. 67, No. 6, 2002
Notes
Ta ble 1. Syn th esis of Secon d a r y Am in es via
decrease in reactivity was observed for sterically less
hindered n-alkyl- and benzylamines. For example, the
obtained yields for addition reactions of n-hexylamine or
benzylamine to diphenylacetylene were below 20% when
Cp2TiMe2 was used as catalyst.7b However, a mechanistic
investigation showed that unfavorable equilibria between
titanium imido complexes, imido complex dimers, and
bisamides which are involved in the catalytic cycle are
responsible for the decreased reactivity of sterically less
demanding amines.9 The mentioned investigation further
suggested that the use of bigger ligands at the titanium
center should result in accelerated reactions of sterically
less demanding amines.
Hyd r oa m in a tion /Red u ction Sequ en ces Em p loyin g
Alk yn es a n d n -Alk yl or Ben zyla m in es a s Sta r tin g
Ma ter ia ls
Since the pentamethylcyclopentadienyl ligand (Cp*) is
much more space demanding than the cyclopentadienyl
ligand (Cp), we decided to investigate the catalytic
properties of Cp*2TiMe2.10,11 In an initial experiment,
diphenylacetylene 1 (1.0 equiv) was reacted with n-
propylamine 4 (1.1 equiv) in the presence of 6.0 mol %
Cp*2TiMe2 at 114 °C (oil bath temperature) in toluene.
TLC-control showed that the reaction reached 100%
conversion after 4 h. After subsequent reduction per-
formed with zinc-modified NaBH3CN12 in methanol at 25
°C the amine 9 was isolated in 86% yield (Table 1, entry
1). In comparison, an identical hydroamination reaction
performed with 6.0 mol % Cp2TiMe2 did not even reach
100% conversion after 48 h. In this case, the subsequent
reduction gave access to only 10% of the desired amine
9. Furthermore, 65% of diphenylacetylene 1 could be
recovered (Table 1, entry 4). While the hydroamination
reaction was very clean in the presence of Cp*2TiMe2,
several side products were observed in the case of
Cp2TiMe2. A similar behavior was observed for the
addition of p-methoxybenzylamine 5 (PMB-NH2) to di-
phenylacetylene 1 followed by reduction. With Cp*2TiMe2
as the catalyst, the hydroamination reaction went to
completion within 6 h. After reduction, the corresponding
amine 10 was obtained in 97% yield (Table 1, entry 5).
In the case of Cp2TiMe2, the same hydroamination did
not reach 100% conversion after 48 h. After reduction, a
sluggish reaction mixture was obtained. Purification by
chromatography afforded 65% of recovered diphenyl-
acetylene 1. However, isolation of the desired amine 10
was not possible in pure form (Table 1, entry 6). In an
additional hydroamination/reduction sequence employing
1 and n-hexylamine 6, the secondary amine 11 was
formed in 89% yield (Table 1, entry 7). In this case, the
hydroamination reaction was complete after 5 h (TLC
control). Inspired by the mentioned results, we tried to
minimize the amount of the hydroamination catalyst for
the representative reaction sequence between 1 and 4
a
b
Reaction time of the hydroamination step. Reaction condi-
tions: (a) alkyne (2.40 mmol), amine (2.64 mmol), catalyst (2.0-
6.0 mol %), toluene (1.0 mL), 114 °C; (b) NaBH3CN (4.80 mmol),
ZnCl2 (2.40 mmol), MeOH (10.0 mL), 25 °C, 20 h. c 65% diphen-
d
ylacetylene 1 could be recovered. The product could not be
isolated in pure form. e The reaction time has not been minimized.
(Table 1, entries 2 and 3). During this study, we found
that a catalyst loading of 2.0 mol % Cp*2TiMe2 is
sufficient to obtain 9 in excellent yield (89%, 12 h reaction
time of the hydroamination step at 114 °C). However, in
several experiments, no complete conversion was ob-
served with catalyst loadings below 2.0 mol %. The reason
for this is probably hydrolysis of the catalyst caused by
trace amounts of water present on the glassware or in
the starting materials.
With the mentioned results in mind, we tried to react
the dialkylalkynes 3-hexyne 2 and 4-octyne 3 with
various benzyl- and n-alkylamines. In all investigated
reaction sequences (Table 1, entries 8-11), the desired
amines (12-15) were obtained in high yields (78-91%).
Due to the low boiling points of 3-hexyne 2 and 4-octyne
(6) (a) Petasis, N. A. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; J ohn Wiley & Sons: New York, 1995;
Vol. 1, pp 470-473. (b) Siebeneicher, H.; Doye, S. J . Prakt. Chem. 2000,
342, 102-106.
(7) (a) Haak, E.; Doye, S. DE 199 13 522, 1999. (b) Haak, E.;
Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed. Engl. 1999, 38, 3389-
3391. (c) Haak, E.; Siebeneicher, H.; Doye, S. Org. Lett. 2000, 2, 1935-
1937.
(8) Bytschkov, I.; Doye, S. Eur. J . Org. Chem. 2001, 4411-4418.
(9) Pohlki, F.; Doye, S. Angew. Chem., Int. Ed. Engl. 2001, 40, 2305-
2308.
(10) Bercaw, J . E.; Marvich, R. H.; Bell, L. G.; Brintzinger, H. H. J .
Am. Chem. Soc. 1972, 94, 1219-1238.
(11) The Ti(IV) imido complex Cp*2TidNPh has been described in:
Polse, J . L.; Andersen, R. A.; Bergman, R. G. J . Am. Chem. Soc. 1998,
120, 13405-13414.
(12) Kim, S.; Oh, C. H.; Ko, J . S.; Ahn, K. H.; Kim, Y. J . J . Org.
Chem. 1985, 50, 1927-1932.

Notes
J . Org. Chem., Vol. 67, No. 6, 2002 1963
Ta ble 2. Obser ved Regioselectivity for Hyd r oa m in a tion /
Red u ction Sequ en ces Em p loyin g 1-P h en ylp r op yn e 16
Finally, we focused on reactions of terminal alkynes.
For that purpose, we performed hydroamination reac-
tions with phenylacetylene, p-methoxyphenylacetylene
and 1-hexyne in the presence of 6.0 mol % Cp*2TiMe2 at
114 °C employing the amines 5 and 6 (reaction times
1-24 h). However, after reduction we were not able to
isolate any hydroamination products from the obtained
complex reaction mixtures. In all investigated reactions,
several new products without an amine function were
formed (probably by alkyne oligo- or polymerization).
In summary, the presented results clearly indicate that
Cp*2TiMe2 represents an excellent catalyst for the inter-
molecular addition of various sterically less hindered
n-alkyl- and benzylamines to internal alkynes. Therefore,
the developed procedure strongly expands the scope of
the titanocene-catalyzed intermolecular hydroamination
of alkynes. The imines, initially obtained from the hy-
droamination reactions, can be reduced with NaBH3CN
in the presence of ZnCl2 to give secondary amines in high
yields. If the unsymmetrically disubstituted alkyne 1-phen-
ylpropyne is used, mixtures of regioisomers are obtained.
Further investigations dealing with the addition of
ammonia to alkynes are currently underway in our
laboratories.
a
Reaction conditions: (a) alkyne (2.40 mmol), amine (2.64
mmol), Cp*2TiMe2 (3.0 or 6.0 mol %), toluene (1.0 mL), 114 °C, 24
h (not minimized); (b) NaBH3CN (4.80 mmol), ZnCl2 (2.40 mmol),
MeOH (10.0 mL), 25 °C, 20 h.
Exp er im en ta l Section
All reactions were performed under an inert atmosphere of
argon in flame dried Duran glassware (e.g., Schlenk tubes
equipped with Teflon stopcocks). Toluene was distilled from
molten sodium under argon. Methanol was distilled and stored
over molecular sieves (4 Å). Cp*2TiMe2 was synthesized accord-
ing to a literature procedure.10 Diphenylacetylene 1 was dis-
solved in CH2Cl2, dried over Na2SO4, and recovered by evapo-
ration of the solvent. The alkynes 2 and 3 as well as the amines
4-8 were distilled and stored over molecular sieves (4 Å). All
other reagents were purchased from commercial sources and
were used without further purification. PE: light petroleum, bp
40-60 °C.
Gen er a l P r oced u r e. A Schlenk tube equipped with a Teflon
stopcock and a magnetic stirring bar was charged with the
alkyne (2.40 mmol), the amine (2.64 mmol), Cp*2TiMe2 (50 mg,
0.144 mmol, 6.0 mol %), and toluene (1.0 mL). The resulting
mixture was heated to 114 °C (oil bath temperature; reaction
times are given in the following paragraphs, Tables 1 and 2,
and the Supporting Information). Then the mixture was cooled
to room temperature, and a suspension of NaBH3CN (302 mg,
4.80 mmol) and ZnCl2 (326 mg, 2.40 mmol) in methanol (10 mL)
was added. After being stirred for 20 h at room temperature,
the mixture was filtered. The solid residue was washed with
CH2Cl2 (50 mL), and saturated Na2CO3 solution (20 mL) was
added to the filtrate. After extraction, the organic layer was
separated. The aqueous layer was extracted with CH2Cl2 (6×
50 mL). The combined organic layers were dried over Na2SO4.
Evaporation of the solvent under vacuum and flash chromatog-
raphy on silica gel afforded the pure amine derivative.
Am in e 9. The general procedure was used to convert 1 and 4
into the title compound. The reaction time of the hydroamination
step was 4 h. Purification by flash chromatography (PE/EtOAc,
3:1) afforded amine 9 (494 mg, 2.06 mmol, 86%) as colorless oil:
IR (neat) ν 1602, 1494, 1453, 756, 696 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.10-7.35 (m, 10H), 3.83 (dd, J ) 5.9, 8.0 Hz, 1H),
2.93 (dd, J ) 5.9, 13.4 Hz, 1H), 2.88 (dd, J ) 8.2, 13.4 Hz, 1H),
2.28-2.41 (m, 2H), 1.51 (br. s, 1H), 1.37 (sex, J ) 7.3 Hz, 2H),
0.76 (t, J ) 7.4 Hz, 3H); 13C NMR (100.6 MHz, DEPT, CDCl3) δ
144.1 (C), 139.0 (C), 129.2 (CH), 128.3 (CH), 128.2 (CH), 127.3
(CH), 126.9 (CH), 126.3 (CH), 64.8 (CH), 49.6 (CH2), 45.3 (CH2),
23.1 (CH2), 11.6 (CH3); MS (25 °C) m/z 239 (2) [M+], 148 (100)
[M+ - C7H7]. Anal. Calcd. for C17H21N: C, 85.31; H, 8.84; N,
5.85. Found: C, 84.91; H, 8.82; N, 5.88.
3, hydroamination reactions employing these alkynes
have not been followed by TLC control. Therefore, the
reaction times have not been minimized. All of these
reactions were stopped after 24 h. Subsequently, the
obtained reaction mixtures were reduced under standard
conditions to give the desired products.
On the basis of these results, we focused on reactions
of the unsymmetrically substituted alkylarylalkyne 1-
phenylpropyne 16. Hydroamination/reduction sequences
using Cp*2TiMe2 as hydroamination catalyst were per-
formed with p-methoxybenzyl- 5, n-hexyl- 6, and benzyl-
amine 7 in toluene. All hydroamination reactions were
performed at 114 °C (oil bath temperature). The reaction
time was always 24 h (not minimized). The catalyst
loading was 3.0 or 6.0 mol %. As can be seen from Table
2, mixtures of regioisomers were isolated from all men-
tioned reaction sequences (Table 2, entries 1-3). While
the observed regioselectivities are low, the obtained yields
of both regioisomers are high (82-94%) and the anti-
Markovnikov products (17a , 18a , 19a ) represent the
major product in all three investigated examples.
In addition, a control experiment employing the steri-
cally more demanding amine 4-methylaniline 20 (p-Tol-
NH2) was carried out in the presence of Cp*2TiMe2 (Table
2, entry 4). Interestingly, in this case the anti-Markovni-
kov product 21a was isolated in 92% yield and only trace
amounts of the regioisomeric product 21b (3%) were
obtained (yield (21a + 21b) 95%, selectivity ∼ 97:3). An
additional experiment employing amine 20 gave access
to a comparable mixture of regioisomers (yield (21a +
21b) 95%, selectivity ∼98:2) when Cp2TiMe2 was used
as the catalyst under identical conditions. These results
indicate that obviously the properties of the employed
amines (and not the Cp*-ligands) are responsible for the
low regioselectivity of Cp*2TiMe2-catalyzed hydroamina-
tion reactions performed with sterically less demanding
n-alkyl- and benzylamines.
Am in e 13. The general procedure was used to convert 2 and
7 into the title compound. The reaction time of the hydroami-

1964 J . Org. Chem., Vol. 67, No. 6, 2002
Notes
nation step was 24 h. Purification by flash chromatography (PE/
to the Deutsche Forschungsgemeinschaft, the Fonds der
Chemischen Industrie and Bayer AG for financial
support.
EtOAc, 5:1) afforded amine 13 (399 mg, 2.09 mmol, 87%) as
colorless oil: IR (neat) ν 1603, 1494, 1454, 731, 696 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 7.17-7.35 (m, 5H), 3.77 (d, J ) 13.1
Hz, 1H), 3.74 (d, J ) 13.1 Hz, 1H), 2.50 (quin, J ) 5.8 Hz, 1H),
1.26-1.52 (m, 7H), 0.90 (t, J ) 7.3 Hz, 3H), 0.89 (t, J ) 7.4 Hz,
3H); 13C NMR (100.6 MHz, DEPT, CDCl3) δ 141.1 (C), 128.3
(CH), 128.1 (CH), 126.7 (CH), 57.8 (CH), 51.2 (CH2), 35.9 (CH2),
26.2 (CH2), 18.9 (CH2), 14.4 (CH3), 9.8 (CH3); MS (25 °C) m/z
191 (4) [M+], 162 (72) [M+ - C2H5], 148 (72) [M+ - C3H7], 91
(100) [C7H7+]. Anal. Calcd. for C13H21N: C, 81.62; H, 11.06; N,
7.32. Found: C, 81.31; H, 11.36; N, 7.72.
Su p p or t in g In for m a t ion Ava ila b le: Experimental
details and characterization data for compounds 10, 11, 12,
14, 15, 17a , 17b, 18a , 18b, 19a , 19b, 21a and 21b (6 pages).
This material is available free of charge via the Internet at
http://pubs.acs.org. This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Ack n ow led gm en t. We thank Prof. E. Winterfeldt
for his generous support of our research. We are grateful
J O016311P