Ti(NMe2)4-catalyzed Markovnikov hydroamination of alkynes in the presence of N-heterocyclic carbenes and LiN(SiMe3)2

Article abstract of DOI:10.1016/j.tetlet.2006.08.042

Intermolecular hydroamination of alkynes catalyzed by Ti(NMe₂)₄ was much improved with N-heterocyclic carbenes and LiN(SiMe₃)₂, by which high Markovnikov selectivity was attained for the coupling of nearly all a

Full text of DOI:10.1016/j.tetlet.2006.08.042

Tetrahedron Letters 47 (2006) 7335–7337
Ti(NMe2)4-catalyzed Markovnikov hydroamination of alkynes
in the presence of N-heterocyclic carbenes and LiN(SiMe3)2
Ken Takaki,* Sadayuki Koizumi, Yuta Yamamoto and Kimihiro Komeyama
Department of Chemistry and Chemical Engineering, Graduate School of Engineering, Hiroshima University, Kagamiyama,
Higashi-Hiroshima 739-8527, Japan
Received 18 July 2006; revised 4 August 2006; accepted 7 August 2006
Available online 1 September 2006
Abstract—Intermolecular hydroamination of alkynes catalyzed by Ti(NMe2)4 was much improved with N-heterocyclic carbenes and
LiN(SiMe3)2, by which high Markovnikov selectivity was attained for the coupling of nearly all alkynes and amines.
Ó 2006 Elsevier Ltd. All rights reserved.
Hydroamination of alkynes and alkenes has been recog-
nized as an important process for the synthesis of many
higher nitrogen compounds in an atom-economical
manner, and thus, various catalytic systems have been
extensively explored, which include lanthanides and
actinides, early and late transition metals as well as base
catalysts.1 For the intermolecular reaction of alkynes,
group IV catalysts, particularly titanium complexes,
have been successfully used since the pioneering work
of Bergman and co-workers.2 However, general Ti cata-
lysts applicable to a wide range of alkynes and amines
are still limited.3 With respect to the regiochemistry of
the reaction, anti-Markovnikov products are preferen-
tially obtained with titanocene catalysts, and in contrast,
Markovnikov isomers with nontitanocenes in general.
The selectivity is, however, dramatically altered by the
change of the alkynes, amines, and metal ligands.
Accordingly, there are a few regiospecific systems for
all substrates.4
Ti-catalysts,7 the NHC ligands would facilitate the gen-
eration of a Ti-imido complex, an active species of the
reaction, from the bisamide precursor and prevent its
dimerization. Regiochemistry may also be changed by
the steric and electronic effect of the ligand.8 With these
expectations, we studied the effect of NHCs on the
intermolecular hydroamination of alkynes catalyzed by
titanium complexes.
When the reaction of 1-octyne (6a) with aniline (7a) was
carried out using Ti(NMe2)4 (1) and NHC 4a, which is
generated in situ from 1,3-dimethylimidazolium iodide
and LiN(SiMe3)2 (5a), total yields of the products, 8a
and 9a, were variable depending on the equivalent of
5a: excess addition (2–3 equiv) usually gave better yields.
Thus, the isolated NHCs 49 were used to evaluate their
effect accurately (Table 1).
Ti(NMe2)4
CpTi(NMe2)3
Ti(CH2Ph)4
1
2
3
N-Heterocyclic carbenes (NHCs) have attracted much
attention recently, because they can stabilize and acti-
vate the catalysts through specific coordination to the
metal center, giving rise to revolutionary results in
homogeneous catalysis chemistry.5 A couple of tita-
nium–NHC complexes have been reported,6 but their
reactivity for hydroamination is not investigated,
surprisingly. Considering the reaction mechanism with
••
R
N
R N
M-N(SiMe3)2
5a: M = Li
5b: M = Na
5c: M = K
4a: R = Me
4b: R = 2,4,6-Me3Ph
While the reaction with catalyst 1 alone gave the prod-
ucts in 42% yield, addition of the NHCs, 4a and 4b,
rather decreased the reaction efficiency (runs 1–3). Inter-
estingly, the yield was much improved to 82% in the
presence of equimolar amounts of 1, 4a, and lithium
silylamide 5a (run 5). Control reaction using 1 and 5a
Keywords: Hydroamination; Alkynes; Titanium catalysts; N-Hetero-
cyclic carbenes; Lithium silylamides.
*
Corresponding author. Tel.: +81 82 424 7744; fax: +81 82 424
5494; e-mail: ktakaki@hiroshima-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.042

7336
K. Takaki et al. / Tetrahedron Letters 47 (2006) 7335–7337
Table 1. Effect of the Ti-catalysts 1–3, NHCs 4, and silylamides 5a
Ti-catalysts 1-3
Table 2. The reaction of various alkynes with anilinea
NPh
NPh
R2
NPh
NPh
cat: 1 + 4b + 5a
R2
1
R1
R2
PhNH2
(10 mol%)
+
+
R
R1
+
+
Hex
Hex
H
PhNH2
NHCs 4
silylamides 5
Hex
H
8
9
6
7a
8a
9a
6a
7a
(when R1= R2, > 99 : 1)
Run Ti-catalyst NHC Silyamide Ratio of Total yield
Run Alkyne 6 R1
R2
Product 8 Yieldb (%)
1–3
4
5
1–3/4/5
of 8a and
9ab (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
6a
6b
6c
6d
6e
6f
nHex
H
H
H
H
H
H
H
H
H
8a
8b
8c
8d
8e
8f
92
98
98
54
37
46
68
12
15
57
52
85
32
85
89
nBu
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
3
3
None None
1/0/0
1/1/0
1/1/0
1/0/1
1/1/1
1/1/1
1/2/1
1/1/2
1/2/2
1/1/1
1/1/1
1/1/1
1/1/1
1/0/0
1/2/1
1/0/0
1/2/1
42
33
28
31
82
72
92
45
73
57
48
25
46
53
89
25
85
nOct
c-C6H11
tBu
PhCH2
c-C6H11CH2
TMSOCH2
Et2NCH2
nPr
4a
4b
None
None
None 5a
4a
4b
4b
4b
4b
4a
4b
4a
4b
5a
5a
5a
5a
5a
5b
5b
5c
5c
6g
6h
6i
8g
8h
8i
6j
nPr 8j
H
H
H
Ph
Me 8o
6k
6l
Ph
8k
8l
4-MePh
4-ClPh
Ph
6m
6n
6o
8m
8n
Ph
None None
4b 5a
None None
4b 5a
a Conditions: toluene, 100 °C, 2 h (40 h for run 10, 52 h for run 14, 20 h
for run 15); 7/6 = 3; 1(10 mol %)/4b/5a = 1/2/1.
b Determined by GC and NMR after hydrolysis to the ketone or
aldehyde.
a Conditions: toluene, 100 °C, 2 h; 7a/6a = 3.
b GC yield; the ratio of 8a/9a was not determined.
rinated alkyne 6m was only 32%, and in contrast, it
increased to 85% by the 4-methyl substituent (runs
11–13). Aromatic internal alkynes 6n and 6o gave the
products 8n and 8o in 85% and 89% yields, respectively.
It is noteworthy that nearly perfect Markovnikov selec-
tivity was maintained for all unsymmetrical alkynes 6
irrespective of their product yields.
gave inferior results (run 4). Of course, no hydroamina-
tion took place with 4a and 5a in the absence of 1. The
ratio of the three components, 1, 4, and 5, was found to
be important for the reaction efficiency, that is, the best
yield was obtained when 1/4b/5a was 1/2/1 (runs 6–9).
Clear solvent effect was also observed under the condi-
tions of run 7: toluene (92% yield) > cyclohexane
(52%) > THF (37%) > DMF (28%). Of the silylamide
additives 5, Li salt 5a exhibited superior effect to Na
and K derivatives, 5b and 5c (runs 5, 6 vs 10–13). More-
over, it was proved that the three-component system
was effective not only for the reaction with 1 but also
for those with other Ti-catalysts, 2 and 3 (runs 14–17).
Next, the reaction of 1-octyne (6a) with various amines 7
was carried out using 1, 4b, and 5a (Table 3).10 In the
reaction with aniline derivatives, both electron-donating
and -withdrawing substituents gave good results, except
Table 3. Reaction of 1-octyne with various aminesa
Intermolecular hydroamination of various alkynes 6
with aniline was tested using the three-component
system of 1, 4b, and 5a (Table 2).10 Terminal alkynes
having n-alkyl chains, 6a–6c, gave the Markovnikov
products, 8a–8c, in nearly quantitative yields, wherein
the possible anti-Markovnikov products, 9a–c, were
not detected (runs 1–3). The present system apparently
changed the reactivity and regioselectivity, though the
preferential formation of 8b over 9b (75/25 ꢀ 65/35)
was reported with catalyst 1 alone.11 The product yields
decreased as the primary alkyl groups of 6 were substi-
tuted by secondary and tertiary groups, but the high
regioselectivity was not diminished (runs 4 and 5). While
alkynes 6f and 6g gave the expected products 8f and 8g
in moderate yields (runs 6 and 7), trimethylsilyloxy-
methyl and diethylaminomethyl substituents were not
tolerated under the reaction conditions (runs 8 and 9).
Imine 8j was formed in 57% yield from aliphatic internal
alkyne 6j (run 10). The reactivity of aromatic terminal
alkynes, 6k–m, was very sensitive to the substituents of
the aromatic ring. Thus, the product yield from 4-chlo-
cat: 1 + 4b
+5a
NR
NR
nHex
H
RNH2
nHex
+
+
nHex
H
6a
Run Amine 7
7
8
9
R
Product Total
8, 9
Ratio
yieldb (%) of 8:9b
1
2
3
4
5
6
7
8
9
7p
7q
7r
4-MePh
4-MeOPh
4-FPh
4-ClPh
4-BrPh
8p, 9p
8q, 9q
8r, 9r
8s, 9s
8t, 9t
85
92
93
49
94
53
81
32
92
50
33
23
>99:1
>99:1
>99:1
>99:1
97:3
67:33
>99:1
97:3
>99:1
>99:1
>99:1
>99:1
7s
7t
7u
7v
7w
7x
7y
7z
7a
3,5-Cl2Ph
2,6-Et2Ph
2,6-iPr2Ph
8u, 9u
8v, 9v
8w, 9w
2,4,6-Me3Ph 8x, 9x
10
11
12
nPen
8y, 9y
8z, 9z
8a, 9a
c-C6H11
tBu
a Conditions: toluene, 100 °C, 2 h; 7/6 = 3; 1 (10 mol %)/4b/5a = 1/2/1.
b Determined by GC and NMR after hydrolysis to the ketone or
aldehyde.

K. Takaki et al. / Tetrahedron Letters 47 (2006) 7335–7337
7337
ity for various kinds of alkynes and amines, irrespective
of their product yields.
References and notes
1. For leading reviews, see: (a) Muller, T. E.; Beller, M.
Chem. Rev. 1998, 98, 675–703; (b) Pohlki, F.; Doye, S.
Chem. Soc. Rev. 2003, 32, 104–114; (c) Bytschkov, I.;
Doye, S. Eur. J. Org. Chem. 2003, 935–946; (d) Doye, S.
Synlett 2004, 1653–1672.
2. (a) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am.
Chem. Soc. 1992, 114, 1708–1719; (b) Baranger, A. M.;
Walsh, P. J.; Bergman, R. G. J. Am. Chem. Soc. 1993, 115,
2753–2763.
Figure 1. 1H NMR of the three-component system of 1, 4a, and 5a
(C6D6).
3. For example: Heutling, A.; Pohlki, F.; Doye, S. Chem.
Eur. J. 2004, 10, 3059–3071.
for 4-chloroaniline (7s) and 3,5-dichloroaniline (7u)
(runs 1–6). The reason for the low efficiency of 7s and
7u is unclear at present. Sterically demanding amines
like 7v and 7x afforded the Markovnikov products, 8v
and 8x, in high yields together with no or very little
amounts of the other isomers 9v and 9x, whereas the
2,6-diisopropyl group of 7w disturbed the reaction (runs
7–9). Compared to the original reaction with 1 alone,11
the three-component system improved the reactivity of
aliphatic amines, 7y–a, to a certain extent, but products
yields were still low and decreased in the order of
1° > 2° > 3°-alkyl substituents (runs 10–12). With re-
spect to the regioselectivity, all amines 7 other than 7u
gave the Markovnikov products 8 exclusively.
4. anti-Markovnikov selectivity: (a) Tillack, A.; Castro, I. G.;
Hartung, C. G.; Beller, M. Angew. Chem., Int. Ed. 2002,
41, 2541–2543; (b) Zhang, Z.; Schafer, L. L. Org. Lett.
2003, 5, 4733–4736; Markovnikov selectivity: (c) Cao, C.;
Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 20,
5011–5013; (d) Lorber, C.; Choukroun, R.; Vendier, L.
Organometallics 2004, 23, 1845–1850; See also: (e) Tillack,
A.; Khedkar, V.; Beller, M. Tetrahedron Lett. 2004, 45,
8875–8878.
5. For review, see: Herrmann, W. A. Angew. Chem., Int. Ed.
2002, 41, 1290–1309.
6. (a) Herrmann, W. A.; Ofele, K.; Elison, M.; Kuhn, F. E.;
Roesky, P. W. J. Organomet. Chem. 1994, 480, C7–C9; (b)
Aihara, H.; Matsuo, T.; Kawaguchi, H. Chem. Commun.
2003, 2204–2205; (c) Shukla, P.; Johnson, J. A.; Vidovic,
D.; Cowley, A. H.; Abernethy, C. D. Chem. Commun.
2004, 360–361; (d) Downing, S. P.; Danopoulos, A. A.
Organometallics 2006, 25, 1337–1340.
7. Pohlki, F.; Doye, S. Angew. Chem., Int. Ed. 2001, 40,
2305–2308.
8. Tillack, A.; Jiao, H.; Castro, I. G.; Hartung, C. G.; Beller,
M. Chem. Eur. J. 2004, 10, 2409–2420.
We measured the NMR spectra of the three-component
system to get some information on the active species
generated in situ. At first, Ti-amide 1 was treated with
equimolar amounts of the isolated NHCs, 4a and 4b,
but all 1H and 13C NMR signals of 1 and 4 remained al-
most unchanged. Other titanium complexes 2 and 3 gave
similar results. These observations suggest that the
expected carbene complexes are not formed by this
procedure, which explains the results obtained by the
two-component system of 1 and 4 (Table 1, runs 2 and
3). The failure may be attributed to the four organic
ligands around the Ti(IV) metal, compared to the
successful examples that have at least two Cl ligands
9. Arduengo, A. J., III; Dias, H. V. R.; Harlow, R. L.; Kline,
M. J. Am. Chem. Soc. 1992, 114, 5530–5534.
10. General procedure for the reaction listed in Tables 2 and
3: all manipulations were performed under argon using
standard Schlenk and vacuum line techniques. Toluene
solutions (1 mL each) of NHC 4b (91 mg, 0.3 mmol) and
Li-silylamide 5a (25 mg, 0.15 mmol) were added to the Ti-
amide 1 (33 mg, 0.15 mmol), and the mixture was stirred
for 1 h at room temperature. A mixture of alkyne 6
(1.5 mmol) and amine 7 (4.5 mmol) in toluene (0.5 mL)
was added to the mixture, and stirring was continued for
2 h at 100 °C. The reaction mixture was passed through
Florisil with ether eluent and concentrated in vacuo. GC
confirmed formation of the imine products in comparison
with authentic samples separately prepared. Then, the
mixture was hydrolyzed to ketone or aldehyde by treat-
ment with silica gel in aqueous toluene at room temper-
ature overnight. After addition of dimethyl terephthalate
as an internal standard, the mixture was worked-up and
concentrated in vacuo. Identification of the carbonyl
compounds and determination of their yields were done
1
on the metal.6 On the other hand, the H NMR spectra
of the three components of 1, 4a, and 5a (1/1/1) showed
a significant peak shift (Fig. 1).12 Thus, the original sig-
nal of 1 at d 3.08 split into two parts (d 3.10 and 3.16)
and two signals of 4a at d 3.76 and 7.01 moved to upper
field (d 3.43 and 6.22), respectively, together with a little
downfield shift of 5a (from d 0.09 to 0.20). Although
further work is necessary to elucidate this new species,
it is likely that the NHC moiety close to the Ti metal
would change the reactivity of the original 1 and realize
high regioselectivity.
In summary, we have demonstrated that intermolecular
hydroamination of alkynes with Ti(NMe2)4 (1) was
much improved in the presence of the NHCs 4 and Li-
silylamide 5a, though the nature of the active species
generated in situ is still unclear. This three-component
system exhibited nearly complete Markovnikov selectiv-
1
by GC, GC–MS, and H NMR.
11. (a) Shi, Y.; Ciszewski, J. T.; Odom, A. L. Organometallics
2001, 20, 3967–3969; (b) Ref. 4b.
12. Although Li-silylamide 5a is known to form complexes
with NHCs 4, the present system would produce a
different species by the participation of 1.