Atom-economical synthesis of N-heterocycles via cascade inter-/intramolecular C-N Bond-forming reactions catalyzed by Ti amides

Article abstract of DOI:10.1021/ja101796k

Direct and efficient catalytic reactions with excellent regioselectivity for the preparation of a series of substituted isoindoles, isoquinolines, and imidazoles are reported. Reaction of C₆H₄(2-CN)C≡C-R with an array of amines, catalyzed by 10 mol % of [σ:η¹: η⁵-(OCH₂)(Me₂NCH₂)C ₂B₉H₉]Ti(NMe₂) (1), gives a series of substituted isoindoles in very high yields. In a similar manner, interaction of C₆H₄(2-CH₂CN)C≡C-Ph with various kinds of amines affords a wide range of substituted isoquinolines. On the other hand, treatment of propargylamines (R′C≡CCH₂NHR′′) with nitriles in the presence of 10 mol % of 1 produces a class of substituted imidazoles in high yields. A possible reaction mechanism is proposed, involving sequential inter- and intramolecular C-N bond formation via hydroamination/ cyclization reaction of cyanoalkynes with amines or nitriles with propargylamines catalyzed by titanium amides.

Full text of DOI:10.1021/ja101796k

Published on Web 07/30/2010
Atom-Economical Synthesis of N-Heterocycles via Cascade
Inter-/Intramolecular C-N Bond-Forming Reactions Catalyzed by Ti
Amides
Hao Shen and Zuowei Xie*
Department of Chemistry and Center of NoVel Functional Molecules, The Chinese UniVersity of
Hong Kong, Shatin, N.T., Hong Kong, China
Received July 22, 2009; E-mail: zxie@cuhk.edu.hk
Abstract: Direct and efficient catalytic reactions with excellent regioselectivity for the preparation of a series
of substituted isoindoles, isoquinolines, and imidazoles are reported. Reaction of C6H4(2-CN)CtC-R with
an array of amines, catalyzed by 10 mol % of [σ:η1:η5-(OCH2)(Me2NCH2)C2B9H9]Ti(NMe2) (1), gives a series
of substituted isoindoles in very high yields. In a similar manner, interaction of C6H4(2-CH2CN)CtC-Ph
with various kinds of amines affords a wide range of substituted isoquinolines. On the other hand, treatment
of propargylamines (R′CtCCH2NHR′′) with nitriles in the presence of 10 mol % of 1 produces a class of
substituted imidazoles in high yields. A possible reaction mechanism is proposed, involving sequential
inter- and intramolecular C-N bond formation via hydroamination/cyclization reaction of cyanoalkynes with
amines or nitriles with propargylamines catalyzed by titanium amides.
complexes,6 important ligands in metalloenzymes,7 precursors
to ionic liquids,8 and stable carbenes.9 As a result, preparative
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10.1021/ja101796k  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 11473–11480 11473

A R T I C L E S
Shen and Xie
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11474 J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010

Atom-Economical Synthesis of N-Heterocycles
A R T I C L E S
Scheme 1. Insertion and Amine-Exchange Reactions of 1
reported to be more reactive than their neutral counterparts, the
former are unreactive toward primary aminoalkenes, presumably
owing to the formation of a metal imido species.19
Inspired by the rich chemistry of direct amine addition to
unsaturated organic molecules catalyzed by lanthanides16 and
early transition metal complexes,17-19 and stimulated by our
own work on the reactivity of the neutral group 4 metal
monoamide [σ:η1:η5-(OCH2)(Me2NCH2)C2B9H9]Ti(NMe2) (1)20
and catalytic construction20b,21 and reconstruction of guanidi-
nes,20b,22 we thought catalytic hydroamination may serve as a
new approach for the construction of isoindole, isoquinoline,
and imidazole cores through a proper combination of reactants.
In fact, 1 can be viewed as an isoelectronic/isostructral analogue
of constrained-geometry lanthanide amides or cationic group 4
metal amides.23 The mechanisms of the reactions catalyzed by
1 do not involve any metal imido species.24 It has two different
functional side arms: one strongly bonds to the Ti atom,
preserving the integrity of the constrained-geometry unit, and
the other (amine) coordinates reversibly to the Ti atom,
stabilizing the reactive intermediate. As part of an ongoing
project focused on catalytic hydroamination reactions, we have
recently found that 1 is a very robust catalyst for the cascade
formation of C-N bonds both inter- and intramolecularly,
leading to the formation of substituted isoindoles, isoquinolines,
and imidazoles. These findings are reported in this article.
Scheme 2. Proposed Cascade C-N Bond-Forming Reactions To
Give N-Heterocycles
Results and Discussion
Ti-N bond, subsequently leading to the construction of an
N-heterocycle with the formation of a new Ti-C bond (Scheme
2, eq 1). The Ti-C bond would probably be quenched by an
amine to regenerate a Ti amide and release an N-heterocyclic
molecule.25 On the basis of this scenario, the synthesis of
N-heterocycles from reactions of cyanoalkynes with amines
(Scheme 2, eq 2) and aminoalkynes with nitriles (Scheme 2,
eq 3) catalyzed by 1 would be feasible. With this in mind, we
examined the reactions of several cyanoalkynes (2) with amines
(3) and propargylamines (7) with nitriles (8) in the presence of
catalytic amounts of 1 and other metal amides.
Substituted Isoindoles. A model reaction of C6H4(2-CN)-
CtC-Ph (2a) with cyclohexylamine (3a) was initially examined
in C6D6 (Table 1). There was no detectable reaction observed
in the absence of a catalyst at 115 °C after prolonged heating
in a sealed NMR tube (entry 1). Alkali metal salts showed no
catalytic activity for this reaction (entries 2 and 3). However,
addition of 10 mol % of group 4 metal amides resulted in the
formation of cyclohexylamine-substituted isoindole derivative
4a (entries 4-7). Among these metal amides, the Ti species
was the most catalytically active (entries 4-6), probably due
to its high Lewis acidity, facilitating the coordination of
substrates. The catalytic activities of 1 and Ti(NMe2)4 are almost
the same (entries 6, 7 vs 9, 10). The reaction temperature was
optimized at 115 °C since the reaction was slow at lower
temperatures, for example, 80 °C (entries 6 and 9). Lower
catalyst loading (5 mol %) resulted in a slower reaction or a
lower yield (entries 8 and 11).
General Consideration. We have recently prepared a neutral
group
4
metal monoamide, [σ:η1:η5-(OCH2)(Me2NCH2)-
C2B9H9]Ti(NMe2) (1), in 91% isolated yield by treatment of
[Me3NH][µ-7,8-CH2OCH2-7,8-C2B9H10] with Ti(NMe2)4 in tolu-
ene.20 It is found that benzonitrile (NtC-Ph) can insert into
the Ti-N bond in 1 to generate the amidinate complex [σ:η1:
η5-(OCH2)(Me2NCH2)C2B9H9]Ti-[NdC(Ph)NMe2],20 and 1 can
readily react with amines to afford new titanacarborane amides
via amine-exchange reactions (Scheme 1).20-22 However, 1
cannot catalyze the hydroamination reaction of nitriles, as the
resulting titanacarborane amidinate complexes do not react with
amines.
It is anticipated that the incorporation of a CtC unit in the
resultant amidinate complex would possibly result in the
intramolecular insertion of the CtC bond into the newly formed
(18) For examples, see: (a) Wood, M. C.; Leitch, D. C.; Yeung, C. S.;
Kozak, J. A.; Schafer, L. L. Angew. Chem., Int. Ed. 2007, 46, 354–
358. (b) Majumder, S.; Odom, A. L. Organometallics 2008, 27, 1174–
1177. (c) Bexrud, J. A.; Beard, J. D.; Leitch, D. C.; Schafer, L. L.
Org. Lett. 2005, 7, 1959–1962. (d) Mu¨ller, C.; Loos, C.; Schulenberg,
N.; Doye, S. Eur. J. Org. Chem. 2006, 2499–2503. (e) Kim, H.; Lee,
P. H.; Livinghouse, T. Chem. Commun. 2005, 5205–5207. (f)
Thomson, R. K.; Bexrud, J. A.; Schafer, L. L. Organometallics 2006,
25, 4069–4071. (g) Watson, D. A.; Chiu, M.; Bergman, R. G.
Organometallics 2006, 25, 4731–4733. (h) Gott, A. L.; Clarke, A. J.;
Clarkson, G. J.; Scott, P. Organometallics 2007, 26, 1729–1737. (i)
Gott, A. L.; Clarke, A. J.; Clarkson, G. J.; Scott, P. Chem. Commun.
2008, 1422–1424.
(19) For examples, see: (a) Gribkov, D. V.; Hultzsch, K. C. Angew. Chem.,
Int. Ed. 2004, 43, 5542–5546. (b) Knight, P. D.; Munslow, I.;
O’Shaughnessy, P. N.; Scott, P. Chem. Commun. 2004, 894–895.
(20) (a) Shen, H.; Chan, H.-S.; Xie, Z. Organometallics 2007, 26, 2694–
2704. (b) Shen, H.; Xie, Z. J. Organomet. Chem. 2009, 694, 1652–
1657.
We then extended the substrate scope to include other amines
and cyanoalkynes in the presence of 10 mol % of titanium
amides. The corresponding results are given in Table 2. It was
found that Ti(NMe2)4 and 1 were almost equally active in the
reactions of 2a,b with primary amines (entries 1, 2, and 8). On
the other hand, Ti(NMe2)4 exhibited a lower activity than 1 in
(21) Shen, H.; Chan, H.-S.; Xie, Z. Organometallics 2006, 25, 5515–5517.
(22) Shen, H.; Xie, Z. Organometallics 2008, 27, 2685–2687.
(23) (a) Xie, Z. Coord. Chem. ReV. 2006, 250, 259–272. (b) Braunschweig,
H.; Breitling, F. M. Coord. Chem. ReV. 2006, 250, 2691–2720. (c)
Li, X.; Hou, Z. Coord. Chem. ReV. 2008, 252, 1842–1869.
(24) Reactions of 1 with both primary and secondary amines give Ti amido
species, see refs 20-22.
(25) Intermolecular reaction of M-C/N bond with amine has been reported,
see refs 16-19.
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J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010 11475

A R T I C L E S
Shen and Xie
Table 1. Effects of Metal Catalysts on Reaction of 2a with 3a
Scheme 3. Isomerization between E-4 and Z-4
open coordination sphere.26 In contrast, two or more NMe2
groups in Ti(NMe2)4 may be displaced by excess amine. As a
result, poor activity was observed for Ti(NMe2)4 in the reactions
with bulkier amines.
It was noted that aromatic amines were not compatible with
these reactions. No obvious reactions of 2a,b with anilines were
observed at lower temperatures in the presence of 10 mol % of
Ti(NMe2)4 or 1. A complex mixture was observed after
prolonged heating, as indicated by 1H NMR. The NMR
experiment also showed a slow decomposition of [σ:η1:η5-
(OCH2)(Me2NCH2)C2B9H9]Ti[NH-C6H4-4-OMe]20a upon heat-
ing a C6D6 solution at 115 °C, whereas 1 was very thermally
stable, and no decomposition was observed after heating at 115
°C for a week.
cat loading
(mol %)
entry
catalyst
temp (°C)
time (h)
yield (%)a
1
2
3
4
5
6
7
8
none
0
10
10
10
10
10
10
5
115
115
115
115
115
80
115
115
80
72
72
72
72
72
72
18
18
72
18
18
0b
0b
NaN(TMS)2
LiN(TMS)2
Hf(NMe2)4
Zr(NMe2)4
Ti(NMe2)4
Ti(NMe2)4
Ti(NMe2)4
1
0b
27
57
76
>95
59
80
9
10
11
10
10
5
1
1
115
115
>95
64
a NMR yield of 4 (E-4 and Z-4) using ferrocene as an internal
standard. b The concentration of 2a remained almost unchanged.
Table 2. Synthesis of Substituted Isoindoles 4
Although Z-isomers were isolated as the final products (except
for E-4f, entry 6 in Table 2), a mixture of both E- and Z-isomers
was observed in NMR experiments for all reactions. In addition,
the NMR results clearly indicated that the major product initially
formed was the E-isomer, which was finally converted to the
Z-isomer under the reaction conditions. Such an isomerization
also proceeded at room temperature in C6D6 in the absence of
any catalysts, which was sped up by heating or treatment with
silica gel. For example, a C6D6 solution of pure E-4f was slowly
converted to a mixture of E-4f and Z-4f in a molar ratio of 65/
35 (E/Z) after standing at room temperature for 5 days. A ratio
of 26/74 (E-4f/Z-4f) was obtained if the solution was heated at
115 °C for 3 days. It was suggested that a zwitterionic
intermediate may be involved in the isomerization (Scheme 3),
and the E/Z ratio was dominated by the thermodynamic stability
of the products. Therefore, the preparative-scale reactions were
all heated at 115 °C in toluene for 120 h and followed by
treatment with silica gel, in order to isolate the more stable
products (Z-isomers) (the last column, Table 2). It was
noteworthy that this reaction proceeded in a 5-exo-dig cycliza-
tion pattern without the observation of any 6-endo-dig product
(Vide infra).
1
All products were fully characterized by H and 13C NMR
spectra and HRMS. The configuration of CdC bonds was
assigned according to NOESY experiments.27 The molecular
structures of Z-4c and Z-4f were further confirmed by single-
crystal X-ray analyses, as shown in Figures 1 and 2.
a NMR yield of 4 (E-4 and Z-4) using ferrocene as an internal
standard. b Isolated product/yield from a preparative-scale reaction.
reactions with five-membered cyclic amines 3c,d (entries 3 and
4). A significant difference was observed in the reactions of
2a,b with bulkier six-membered cyclic amines 3e,f: Ti(NMe2)4
offered the products in <10% yields, whereas 1 gave >95%
yields (entries 5, 6, 9, and 10). Though 1 displayed a moderate
activity in the reaction of 2a with diethylamine (3g), NMR
showed that Ti(NMe2)4 could not catalyze the same reaction
(entry 7). The reasons may be as follows. Complex 1 has only
one active Ti-N σ-bond, and the central Ti atom has a very
Figure 1. Molecular structure of Z-4c.
9
11476 J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010

Atom-Economical Synthesis of N-Heterocycles
A R T I C L E S
Table 4. Synthesis of Substituted Isoquinolines 5 and 6
Figure 2. Molecular structure of Z-4f.
Table 3. Effects of Metal Catalysts on Reaction of 2c with 3a
entry
catalyst
yield (%)a
1
2
3
4
5
6
7
none
0b
0c
NaN(TMS)2
LiN(TMS)2
Hf(NMe2)4
Zr(NMe2)4
Ti(NMe2)4
1
0c
<10
26
>95
>95
a NMR yields of 5/6. b Isolated yields of 5/6 are shown in
parentheses. c Dimethylamino (from the catalyst)-substituted products
5k/6k (R2 ) R3 ) Me) were also observed. d No compound 6 was
isolated.
a NMR yield using ferrocene as an internal standard. b The
concentration of 2c remained unchanged. c Decomposition of 2c was
observed.
Substituted Isoquinolines. In a similar manner, we examined
the reaction of C6H4(2-CH2CN)-CtC-Ph (2c) with cyclohexy-
lamine (3a) to possibly build isoquinoline cores. There was no
detectable reaction observed in the absence of a catalyst upon
heating a C6D6 solution at 115 °C for 80 h (entry 1, Table 3).
Under the same reaction conditions, the decomposition of 2c
was observed in the presence of 10 mol % of strong bases such
as NaN(TMS)2 and LiN(TMS)2 (entries 2 and 3, Table 3), which
might be ascribed to the acidity of benzylic protons in 2c. In
contrast, addition of 10 mol % of group 4 metal amides resulted
in the formation of the desired isoquinoline 5a, and their
activities followed the trend 1 ≈ Ti(NMe2)4 > Zr(NMe2)4 >
Hf(NMe2)4 (entries 4-7, Table 3), probably due to the higher
Lewis acidity of the Ti species.
Various kinds of amines were then examined using Ti(NMe2)4
and 1 as the catalysts. The results are summarized in Table 4.
Reactions of 2c with primary amines 3a,b afforded 5a,b as sole
products, and no 6a,b was observed by NMR (entries 1 and 2).
However, reactions of 2c with cyclic secondary amines 3c,e,f
gave a mixture of 5 and 6, with their ratios mainly dependent
upon the catalysts (entries 3-5). A much better selectivity in
favor of the formation of 5 was observed in the reactions
catalyzed by 1. It was found that, in the case of diethylamine
3g, Ti(NMe2)4 offered <10% NMR yield of 5g, whereas 1 gave
55% NMR yield. After workup, 5g was isolated in 52% yield
in the latter case from a preparative-scale reaction. Ti(NMe2)4
is generally less reactive toward bulkier amines than 1, probably
Figure 3. Molecular structure of 5c.
due to steric effects imposed by several amido groups, as
discussed in the previous reaction. It was noted that the reactions
with aromatic amines were complicated under the same reaction
conditions, which could be ascribed to the thermal instability
of the aforementioned Ti arylamides, and no pure product was
isolated. Excellent regioselectivity in favor of 6-exo-dig products
and the effect of catalysts on the molar ratio of 5/6 will be
discussed in the Reaction Mechanism section.
Products 5 and 6 were fully characterized by 1H and 13C NMR
spectra and HRMS. The solid-state structure of 5c was further
confirmed by single-crystal X-ray diffraction studies as shown
in Figure 3.
Substituted Imidazoles. To explore the generality of group 4
amides in the hydroamination catalysis, an equimolar reaction
of propargylamines (R4CtCCH2NHR5, R4/R5 ) Ph/H, H/H, and
H/Me) with 2-cyanofuran was examined. It was found that no
detectable reaction was observed in C6D6 at 115 °C for 5 h in
the absence of a catalyst (entry 1, Table 5). Some commercially
available or commonly used metal complexes that are known
to be active catalysts in hydroamination reactions28 were also
(26) It has been documented that the coordination number of the Ti atom
in this kind of metallacarboranes can be increased at least by 2 units,
as evidenced by the molecular structure of [σ:η1:η5-(OCH2)-
(Me2NCH2)C2B9H9]Ti[σ:η1-(2-NH-3-CH3-C5H3N)](η1-C5H3N-2-NH2-
3-CH3), see refs 20a, b.
(27) See the Supporting Information for details.
9
J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010 11477

A R T I C L E S
Shen and Xie
Table 5. Effects of Metal Catalysts in Reactions of
Propargylamines with 2-Cyanofuran
Table 6. Synthesis of Substituted Imidazoles 9
entry
R4/R5 (7)
R6 (8)
time (h)
product (9)
yield (%)a
yield (%)a
R4/R5
H/H (7b)
)
1
2
3
4
5
6
7
8
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
Ph/H
H/H
o-furyl- (8a)
o-thiophenyl- (8b)
m-Py- (8c)
5
5
9aa
9ab
9ac
9ad
9ae
9af
9ag
9ah
9ai
92
86
52
61
64
68
66
60
59
63
58
62
51
60
21
34
56
39
36
entry
catalyst
cat (mol %)
Ph/H (7a)
H/Me (7c)
48
48
48
48
48
48
48
48
48
48
48
48
168
168
72
168
168
168
5
1
2
3
4
5
6
7
8
none
0
10
10
10
10
10
10
10
10
10
10
5
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
trace
<20
<20
0
0
0
Ph- (8d)
LiNMe2
LiN(TMS)2
NaN(TMS)2
Ti(NMe2)4
Zr(NMe2)4
Hf(NMe2)4
Cp2TiMe2
Cp2ZrMe2
Cp2HfMe2
1
p-Me-Ph- (8e)
p-MeO-Ph- (8f)
p-CF3-Ph- (8g)
p-F-Ph- (8h)
9
p-Cl-Ph- (8i)
p-Br-Ph- (8j)
m-Me-Ph- (8k)
m-MeO-Ph- (8l)
m-CF3-Ph- (8m)
o-MeO-Ph- (8n)
o-CF3-Ph- (8o)
o-Br-Ph- (8p)
pyrrolyl-(CH2)2- (8q)
cyclo-Pr-CH2- (8r)
i-Pr- (8s)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
9aj
9ak
9al
9
10
11
12
0
>90
74
0
>90
45
9am
9an
9ao
9ap
9aq
9ar
9as
-
9ba
9bb
9bd
9bi
9bn
9bp
9ca
9cd
9cf
>90
47
1
a NMR yield using ferrocene as an internal standard.
examined (entries 2-10, Table 5). Except for M(NMe2)4 (M )
Ti, Zr, Hf), which showed small activities only for 7c (entries
5-7), the others did not offer any of the desired products, and
the concentration of 2-cyanofuran remained almost unchanged.
However, addition of 10 mol % of 1 under the same reaction
conditions resulted in the formation of substituted imidazoles
in >90% NMR yields (entry 11, Table 5). Lower catalyst loading
(5 mol %) resulted in a lower yield under the same conditions
(entry 12, Table 5). It is noteworthy that Ti(NMe2)4 showed
high catalytic activities in the reactions of cyanoalkynes with
amines, as shown in the synthesis of isoindoles and isoquinolines
(Vide supra), but not in the current reactions. These results again
suggest that Ti(NMe2)4 is very sensitive to substrates and that
1 is a very robust catalyst due to its unique molecular structure.29
For metallocenes Cp2MMe2, the presence of two Cp ligands
may block the coordination of the substrates, leading to no
catalytic activity in the reactions.
We then extended the substrate scope to include various
nitriles on a preparative scale. The results are compiled in Table
6. Catalyst 1 exhibited an excellent regioselectivity. Table 6
shows that alkylnitriles, heteroarylnitriles, arylnitriles with
various functional groups at the ortho-, meta-, or para-position,
propargylamines with an internal/terminal CtC bond, and
propargylamines with a mono-/disubstituted amino group are
all compatible with this reaction. The following general trends
were observed: (1) sterically demanding nitriles give much lower
yields (entries 4-13 vs 15 and 16; entry 19 vs 20); (2)
arylnitriles are more reactive than alkylnitriles, as aryl substit-
uents can activate the CtN unit, offering higher yields (entries
1-13 vs 18-20); (3) for ortho-substituted arylnitriles, the donor
substituents facilitate the coordination of a nitrile to the catalyst,
resulting in the faster reaction and higher yields (entry 14 vs
15 and 16; entry 25 vs 26); (4) the nature of substituents on the
phenyl ring does not significantly influence the reactions (entries
b
t-Bu- (8t)
o-furyl- (8a)
-
84
82
28
29
44
24
80
21
25
20
22
H/H
H/H
H/H
H/H
o-thiophenyl- (8b)
Ph- (8d)
p-Cl-Ph- (8i)
o-MeO-Ph- (8n)
o-Br-Ph- (8p)
o-furyl- (8a)
5
60
60
60
60
5
60
60
60
60
H/H
H/Me
H/Me
H/Me
H/Me
H/Me
Ph- (8d)
p-MeO-Ph- (8f)
p-Cl-Ph- (8i)
pyrrolyl-(CH2)2- (8q)
9ci
9cq
a Isolated yield. b No detectable reaction was observed.
4-13, 23, 24, and 28-30); (5) the catalytic system is tolerant
to many functional groups, such as halides, trifluoromethyl,
methoxyl, furyl, thiophenyl, pyridyl, pyrrolyl, and cyclopropyl;
and (6) the reaction proceeds in a 5-exo-dig pattern without the
observation of any 6-endo-dig cyclization products, indicating
an excellent regioselectivity (Vide infra). It is noted that the
reactions of propargylamines with 2-cyanofuran (8a) or 2-cy-
anothiophene (8b) (entries 1, 2, 21, 22, and 27) are much faster
than those with other nitriles and offer very high yields, which
is probably due to the joint effects of the smaller aromatic rings
and the presence of ꢀ-donor atoms (O or S). Compound 8n
shows a much higher reactivity than other ortho-substituted
nitriles (entries 14 and 25), which may be ascribed to the
coordination effect of o-OMe. On the other hand, 7b and 7c
are poorer starting materials than 7a in the reactions with less
reactive nitriles, probably because the terminal alkyne can
quench the [Ti]-C/N bond after prolonged heating, leading to
lower yields (entries 23-26 and 28-31).
The products (9) were fully characterized by H NMR, 13C
NMR, and HRMS. Compound 9ae was further confirmed by
single-crystal X-ray analyses as shown in Figure 4.
1
Reaction Mechanism. In view of the unique structure of 1
(the Ti atom is σ-bonded to only one amido group and strongly
supported by the trianionic ligand [σ:η1:η5-(OCH2)(Me2NCH2)-
C2B9H9]3-), the involvement of any titanium imido (TidN)
species in the aforementioned reactions can be ruled out, as
evidenced by the experimental results shown in Scheme 1.24
(28) For examples, see refs 17a-d,k-n,r,s,18c,d and the following: (a)
Ong, T.-G.; O’Brien, J. S.; Korobkov, I.; Richeson, D. S. Organo-
metallics 2006, 25, 4728–4730. (b) Kubiak, R.; Prochnow, I.; Doye,
S. Angew. Chem., Int. Ed. 2009, 48, 1153–1156.
(29) Many attempts to prepare the Zr and Hf analogues of 1 were not
successful, see ref 20a.
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11478 J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010

Atom-Economical Synthesis of N-Heterocycles
A R T I C L E S
tion of the CtN bond into the Ti-N bond (in 1) and
intramolecular insertion of the CtC triple bond into the newly
formed Ti-N bond (in the amidinate unit Ti-NCN) and
strongly support the formation of the intermediate 1k in Scheme
4.
Given the above experimental results, a possible reaction
pathway for the formation of 4, 5, and 6 is proposed in Scheme
5. Amine-exchange reaction between 1 and 3 generates the
titanacarborane amide A20-22 to enter the catalytic cycle.
Intermolecular insertion of nitrile into the Ti-N bond in A
results in the formation of intermediate B,20 followed by an
intramolecular insertion of the CtC bond into the newly formed
Ti-N bond to afford C.31 The catalytic cycle is completed by
the acid-base reaction of C with amines 3 to regenerate A and
release D.31 D undergoes isomerization to give substituted
isoindoles 4 (n ) 0) or isoquinolines 5 (n ) 1), respectively.
On the other hand, sterically less hindered cyanoalkyne 2c can
further insert into the newly formed Ti-C bond in C to produce
E, during which the steric factor may play a role on the basis
of the fact that the di-insertion was observed only in the case
of 2c but not in 2a,b. Consequently, the constrained-geometry
dicarbollyl ligand may disfavor the second insertion of 2c,
leading to a much better selectivity of 1 over Ti(NMe2)4 in the
reactions of 2c with 3 (Table 4). Intramolecular insertion reaction
of E yields F.31 Protonation between F and 3 regenerates A to
complete the catalytic cycle with the formation of 6′.31 Again,
tautomerization, which is driven by the formation of aromatic
systems, affords products 6. In addition, the insertion of CtC
into the M-N bond is a cis-addition.31 As a result, E-4 products
are initially formed after the metathesis reaction of C (n ) 0)
with 3, which isomerize to the thermodynamically more stable
Z-4 products (Vide supra).
Figure 4. Molecular structure of 9ae.
Scheme 4. Stoichiometric Reactions of 1 with 2a/2c
However, 1 cannot catalyze the direct addition of amines to
nitriles, which implies that the resulting titanacarborane amidi-
nate complexes do not react with amines. On the other hand,
stoichiometric reactions of 1 with 2a or 2c at 75 °C for 4 h (in
the absence of free amines) followed by hydrolysis afforded a
dimethylamino-group-substituted isoindole (Z-4k) or isoquino-
line (5k) in 77% and 61% isolated yields (Scheme 4),
respectively. Many attempts to grow X-ray-quality crystals of
the Ti complexes before the hydrolysis failed. Nevertheless, after
heating a C6D6 solution of 2a and an equimolar amount of 1 at
75 °C for 4 h, the 13C NMR spectrum displayed a characteristic
signal at 209.4 ppm assignable to the R-carbon of the Ti-CdC
unit30 with the disappearance of CtC resonances in the range
80-100 ppm. These observations suggest intermolecular inser-
Scheme 6 shows a possible reaction pathway for the formation
of 9. Amine-exchange reaction between 1 and 7 generates the
titanacarborane amide G to enter the catalytic cycle.20-22
Coordination of nitrile 8 to the Ti atom results in the formation
of H,26 followed by a migratory insertion to give intermediate
Scheme 5. Possible Reaction Mechanism for the Formation of 4, 5, and 6
9
J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010 11479

A R T I C L E S
Shen and Xie
Scheme 6. Possible Reaction Mechanism for the Formation of 9
completed by the acid-base reaction of J with amine 7 to
regenerate G and release 9′.31 9′ undergoes isomerization, which
is favored by the formation of an aromatic system, to produce
substituted imidazole 9. Excellent regioselectivity of these
reactions (in favor of exo-dig-cyclization) can be ascribed to
the constrained geometry of I, which makes the endo-cyclization
impossible.
Conclusion
We have developed new methodologies for the synthesis of
a series of substituted isoindoles, isoquinolines, and imidazoles
with excellent regioselectivity in the presence of a catalytic
amount of titanium amides. This work shows that titanacarbo-
rane monoamide 1 is a very robust catalyst, which is thermo-
dynamically and kinetically very stable and tolerant to many
common functional groups. The unique structure of 1 rules out
the involvement of TidN (titanium imido) species in catalysis.
Thus, a sequential inter- and intramolecular hydroamination
pathway is proposed for the catalytic reactions. Other possible
applications of 1 in catalytic reactions are under investigation.
Acknowledgment. This work was supported by grants from
the Research Grants Council of the Hong Kong Special Administra-
tion Region (Project No. 404609), The Chinese University of Hong
Kong, and CAS-Croucher Funding Scheme for Joint Laboratories.
I.20 Intramolecular insertion of the CtC bond into the newly
formed Ti-N bond affords J.31 Finally, the catalytic cycle is
Supporting Information Available: Complete ref 2j; experi-
mental section; crystallographic data in CIF format for Z-4c,
1
Z-4f, 5c, and 9ae; and H NMR, 13C NMR, NOESY, DEPT-
(30) For examples of the 13C chemical shift of Ti-CdC, see: (a) Selby,
J. D.; Schulten, C.; Schwarz, A. D.; Stasch, A.; Clot, E.; Jones, C.;
Mountford, P. Chem. Commun. 2008, 5101–5103. (b) Wang, H.; Chan,
H.-S.; Xie, Z. Organometallics 2005, 24, 3772–3779. (c) Ward, B. D.;
Maisse-Franc¸ois, A.; Mountford, P.; Gade, L. H. Chem. Commun.
2004, 704–705. (d) Vujkovic, N.; Ward, B. D.; Maisse-Franc¸ois, A.;
Wadepohl, H.; Mountford, P.; Gade, L. H. Organometallics 2007, 26,
5522–5534. (e) Basuli, F.; Aneetha, H.; Huffman, J. C.; Mindiola,
D. J. J. Am. Chem. Soc. 2005, 127, 17992–17993.
135, and HSQC spectra of products. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA101796K
(31) For examples of intramolecular insertion of CtC into the M-N bond
and the subsequent metathesis reaction of M-C bond with N-H bond,
see refs 16a,b,e.
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11480 J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010