Efficient one-pot synthesis of N-Containing heterocycles by multicomponent coupling of silicon-tethered diynes, nitriles, and isocyanides through intramolecular cyclization of iminoacyl-Zr intermediates

Article abstract of DOI:10.1002/chem.201000708

An efficient multicomponent synthesis of 5-azaindoles and dihydropyrrolo[3,2-c]azepines was achieved by zirconocene-mediated coupling of silicon-tethered diynes, nitriles, and isocyanides. The synthesis, structures, and intramolecular cyclization of mono- and bis(iminoacyl)-Zr intermediates were investigated to elucidate the reaction process. Upon hydrolysis, the isolated mono(iminoacyl)-Zr intermediates underwent intramolecular cyclization to afford tetrasubstituted 5azaindoles, whereas intramolecular cyclization of bis(iminoacyl)-Zr intermediates led to the formation of dihydropyrrolo[3,2-c] azepines. The structure of a bis(iminoacyl)-Zr intermediate, formed through insertion of two molecules of CyNC into the Zr-C bond, and structures of two dihydropyrrolo[3,2-c]azepines were characterized by single-crystal X-ray structural analysis.

Full text of DOI:10.1002/chem.201000708

FULL PAPER
DOI: 10.1002/chem.201000708
Efficient One-Pot Synthesis of N-Containing Heterocycles by
Multicomponent Coupling of Silicon-Tethered Diynes, Nitriles, and
À
Isocyanides through Intramolecular Cyclization of Iminoacyl Zr
Intermediates
Shaoguang Zhang,[a] Wen-Xiong Zhang,[a] and Zhenfeng Xi*[a, b]
Dedicated to Professor Uwe Rosenthal on the occasion of his 60th birthday
À
Abstract: An efficient multicomponent
synthesis of 5-azaindoles and
dihydropyrrolo[3,2-c]azepines was ach-
ieved by zirconocene-mediated cou-
pling of silicon-tethered diynes, nitriles,
and isocyanides. The synthesis, struc-
tures, and intramolecular cyclization of
the isolated mono(iminoacyl) Zr inter-
mediates underwent intramolecular
cyclization to afford tetrasubstituted 5-
azaindoles, whereas intramolecular cyc-
mediates led to the formation of
dihydropyrrolo[3,2-c]azepines. The
AHCTUNGTRENNUNG
À
G
structure of a bis(iminoacyl) Zr inter-
mediate, formed through insertion of
À
À
lization of bis(iminoacyl) Zr inter-
two molecules of CyNC into the Zr C
bond,
and
structures
[3,2-c]azepines
of
two
dihydropyrrolo
A
were
Keywords: cyclization · isocyanide
ligands · multicomponent reactions ·
nitrogen heterocycles · zirconium
À
mono- and bis(iminoacyl) Zr inter-
characterized by single-crystal X-ray
structural analysis.
mediates were investigated to elucidate
the reaction process. Upon hydrolysis,
Introduction
À
The insertion of isocyanides into M C bonds is one of the
powerful means for carbon chain construction, and has been
utilized as a key step in organic synthesis.[1–8] The resulting
h2-iminoacyl–metal intermediates in this process, such as h2-
[2,3]
À
iminoacyl Zr complexes,
can be conveniently converted
to one-carbon elongated products such as imines,[7b] aldehy-
des,[7c–f] or nitriles[7g,h] through the cleavage of various chemi-
À
cal bonds, including Zr C, C=N, and N-Rꢀ bonds
2
À
(Scheme 1a). h -Iminoacyl Zr complexes also displayed
other useful reactivities, including reductive elimination
À
Scheme 1. Reactivities of iminoacyl Zr intermediates.
[a] S. Zhang, Prof. Dr. W.-X. Zhang, Prof. Dr. Z. Xi
Beijing National Laboratory for Molecular Sciences (BNLMS)
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, College of Chemistry, Peking University,
Beijing 100871 (China)
(Scheme 1b),[2n] [1,2]-alkyl shift of nonacyl Zr C bonds
À
(Scheme 1c),[4,5f] and other types of rearrangements.[5,6] To
the best of our knowledge, intramolecular cyclization of the
Fax : (+86)10-62751708
E-mail: zfxi@pku.edu.cn
À
iminoacyl Zr intermediates that yields N-containing hetero-
cycles (Scheme 1d) has not been reported.
Pyrrole-fused N-containing heterocycles, such as pyrrolo-
pyridine (azaindoles) and pyrroloazepine analogues, are of
great importance in biochemistry, pharmaceutical science,
and natural product synthesis.[9–14] Thus, development of syn-
[b] Prof. Dr. Z. Xi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, Shanghai 200032 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000708.
Chem. Eur. J. 2010, 16, 8419 – 8426
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8419

thetically useful and highly efficient methods towards these
kinds of N-containing heterocycles is greatly required for
synthetic organic chemistry and the pharmaceutical chemis-
try.[9,10]
We have recently developed a zirconocene-mediated mul-
ticomponent coupling of one molecule of a silicon-tethered
diyne with three nitrile molecules to afford pentasubstituted
5-azaindoles, in which a zirconium- and silicon-containing
of the silicon-tethered diyne and iPrCN (Scheme 2).[15,17]
Treatment of 2a with 1.2 equivalents of aliphatic isocyanide
tBuNC at room temperature for 1 h cleanly led to the
À
mono-insertion of tBuNC into the Zr CACTHNUTRGNEUNG
(sp3) s bond to give
3a in 91% isolated yield (Scheme 2a). Even in the presence
of 2.4 equivalents of tBuNC, only 3a was obtained and the
double-insertion product was not observed, probably owing
to the steric hindrance of tBu group. Similarly, the insertion
of tBuNC into tolyl-substituted 2b gave 3b under the same
conditions (Scheme 2a). However, in the presence of
2.4 equivalents of the less sterically hindered isocyanide
CyNC, the double-insertion product 4 was formed exclusive-
ly in 78% isolated yield (Scheme 2b), showing that the
steric hinderance of isocyanides strongly affects the insertion
reaction. The double-insertion product 5 could also be ob-
tained in good isolated yield when 2.4 equivalents of 2,6-di-
methylphenyl isocyanide were treated with 2a (Scheme 2c).
À
Note that double-insertion of isocyanides into Zr C bonds
is rare, and this work represents an efficient preparation of
[3]
À
bis(iminoacyl) Zr complexes.
2
À
These h -iminoacyl Zr complexes 3a, 3b, 4, and 5 were
all characterized by using H NMR and 13C NMR spectros-
1
copy. The imine carbon atom neighboring the silicon in 3a
showed a singlet at d=186.88 ppm, whereas the characteris-
2
À
tic carbon of the h -iminoacyl Zr moiety displayed a singlet
at d=234.17 ppm in the 13C NMR spectrum in [D6]benzene,
which is shifted down field. The chemical shift of the imi-
À
noacyl Zr carbon in 3a was comparable with those found in
Cp2ZrCl(C
and
A
C
(228.77 ppm).[2o] The two imine carbons of the bis(iminoac-
À
yl) Zr moiety in 4 showed the respective singlets at d=
164.95 and 222.57 ppm in the 13C NMR spectrum, which are
À
consistent with the data for a reported bis(iminoacyl) Zr
complex.[3d] Compared with the mono(iminoacyl) Zr carbon
À
À
Scheme 2. Formation of iminoacyl Zr complexes by insertion of isocya-
in 3a, the iminoacyl carbon in 4 (222.57 ppm) appeared to
be shifted upfield in the 13C NMR spectrum, probably owing
to the electron-withdrawing effect of the adjacent imino
group. Similar to 4, the two imine carbon atoms of the bis-
À
nides into the Zr C
(sp3) bond.
À
intermediate with three fused rings (Scheme 2, complex 2)
was isolated and structurally characterized.[15,16] In this
paper we report zirconocene-mediated multicomponent cou-
pling of silicon-tethered diynes, nitriles, and isocyanides to
afford the formation of azaindoles or dihydropyrroloACHTUNTRGNEUNG[3,2-
c]azepines efficiently. The isolation, structural characteriza-
tion, and intramolecular cyclization of mono- and bis(imi-
noacyl) Zr intermediates enables us to understand the pro-
cess of such a multicomponent coupling reaction.
ACHTUNGTREN(NUNG iminoacyl) Zr moiety in 5 showed two singlets at d=
180.93 and 237.10 ppm in the 13C NMR spectra.
The structure of 4 was confirmed by single-crystal X-ray
structural analysis, which featured a four-ring fused structure
(Figure 1). The zirconium center is bound to an h2-iminoacyl
moiety in an edge-on fashion, featuring a three-membered
azazirconacycle.[18] The Zr1 N4 bond of 2.245(2) ꢂ and the
À
À
À
À À
Zr C18 bond of 2.175 (3) ꢂ in the Zr C N three-mem-
bered ring are close to the value of the reported bis(imi-
noacyl) Zr complex.[3d] The Zr1 N4 bond length of
À
À
À
2.245(2) ꢂ is even shorter than the Zr1 N1 s bond of
2.347(2) ꢂ, indicating a strong coordinative driving effect
Results and Discussion
between the Zr1 and N4 atoms. The bond lengths of the two
À
À
À
Isolation and structural characterization of iminoacyl Zr
imine bonds C17 N3 and C18 N4 are 1.276(4) and
1.254(3) ꢂ, respectively, demonstrating strong C=N double-
bond character.
À
and bis(iminoacyl) Zr intermediates through mono- and
double-insertion of isocyanides into azazirconacycles: Green
(sp3) s bond could be iso-
ACHTUNGTRENNUNG
À
solids 2 that have a reactive Zr C
lated in high yields from the zirconocene-mediated coupling
8420
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8419 – 8426

À
Intramolecular Cyclization of Iminoacyl Zr Intermediates
FULL PAPER
2
À
These isolated h -iminoacyl Zr complexes were not nec-
essarily required for the formation of 5-azaindoles. In fact,
5-azaindoles could be prepared conveniently in one-pot
through the zirconocene-mediated multicomponent coupling
of silicon-tethered diynes, nitriles, and isocyanides as shown
in Table 1. When bisACTHNUTRGNE(NUG alkynyl)silane 1a, iPrCN, and tBuNC
were used, tetrasubstituted 5-azaindole 6a was formed in
63% isolated yield, with only the isocyanide carbon atom
being integrated into the product (Table 1, entry 1). The
Table 1. Formation of 5-azaindoles 6 through zirconocene-mediated mul-
ticomponent coupling of silicon-tethered diynes, nitriles, and isocyanides.
Figure 1. ORTEP drawing of 4 with 30% thermal ellipsoids. Hydrogen
À
atoms are omitted for clarity. Selected bond length [ꢂ]: Zr1 N1 2.347(2),
À
À
À
À
Zr1 N4 2.245(2), Zr1 C18 2.175(3), Si1 C15 1.924(3), Si1 N2 1.744(3),
À
À
À
À
C13 C16 1.389(4), C15 C16 1.539(4), C15 C17 1.521(4), C17 C18
À
À
1.470(4), C17 N3 1.276(4), C18 N4 1.254(3).
Entry bis
G
R’NC
Product 6 (yield
[%])[a]
2
À
Intramolecular cyclization of h -iminoacyl Zr complexes to
N-containing cyclic compounds
1
tBuNC
The one-pot formation of tetra-substituted 5-azaindoles from
a silicon-tethered diyne, two nitrile molecules, and one isocya-
nide: Conversion of h2-iminoacyl-Zr complexes to functional
organic molecules is of important interest both for organic
synthesis and for organometallic chemistry. Hydrolysis of
the mono-insertion product 3a with H2O afforded a tetra-
1a
1a
6a (63)
2
3
CyNC
6a (65)[b]
2,6-
Me2PhNC
1a
6a (54)
substituted 5-azaindole derivative 6a in>90% NMR yield,
2
4
5
6
7
1a
CyNC
tBuNC
tBuNC
tBuNC
À
showing that the h -iminoacyl Zr moiety cyclized with the
À
N-silyl imine moiety in an unexpected C N bond-forming
fashion (Scheme 3). Together with 6a, formation of tBuNH2
after quenching with water was detected by using GC–MS.
In addition, the Cp2Zr moiety and the SiMe2 moiety were
coupled to form the cyclic zirconasiloxane 7 (see the Sup-
porting Information for more details).
6b (55)
6c (66)
1a
1b
1b
6d (41)
6e (53)
8
1b
tBuNC
6 f (46)
[a] Isolated yields. [b] Yield of main product, with trace amounts of other
products.
À
Scheme 3. Hydrolysis of the iminoacyl Zr intermediates 3a.
Chem. Eur. J. 2010, 16, 8419 – 8426
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8421

Z. Xi et al.
newly formed carbon–hydrogen bond was found to originate
from the hydrolysis process.[15b] Changing the isocyanide
from tBuNC to both aliphatic CyNC and aromatic 2,6-dime-
thylphenyl isocyanide led to the same 5-azaindole 6a as the
main product in 65 and 54% yields, respectively (Table 1,
entries 2 and 3). In addition to iPrCN, the scope of nitriles
could be expanded to 2-methylbutyronitrile (Table 1, entry 4
and 7), CyCN (Table 1, entry 5), and 1-phenyl cyclopropane-
carbonitrile (Table 1, entry 8), affording their corresponding
tetrasubstituted 5-azaindoles 6b–f in moderate to good iso-
lated yields. All these examples demonstrate that this zirco-
nocene-mediated multicomponent coupling reaction is
useful for the synthesis of tetrasubstituted 5-azaindoles
ꢀ
through cleavage of the N C triple bond in isocyanide.
Figure 2. ORTEP drawing of 8a with 30% thermal ellipsoids. Hydrogen
The formation of dihydropyrroloACTHNUGRTNEUNG[3,2-c]azepine derivatives
À
atoms are omitted for clarity except for the polar N H bonds.
from a silicon-tethered diyne, two nitrile molecules, and two
isocyanide molecules: When the reaction mixture containing
the double-insertion intermediate 5 was hydrolyzed with
water, two dihydropyrroloACTHNURTGNEU[GN 3,2-c]azepine derivatives 8a and
9a were obtained in 46 and 24% yields, respectively
(Scheme 4). Single-crystal X-ray structural analysis of 8a
Figure 3. ORTEP drawing of 9a with 30% thermal ellipsoids. Hydrogen
À
atoms are omitted for clarity except for the polar N H bonds and the ter-
À
tiary C47 H bond.
ered diyne, two nitrile molecules, and two molecules of iso-
cyanide is of great synthetic value.
À
Scheme 4. Intramolecular cyclization of bis(iminoacyl) Zr complexes to
form dihydropyrroloACHTUNGTRENNUNG[3,2-c]azepines.
Conclusion
and 9a demonstrated their pyrrole-fused seven-membered
In summary, we have developed an efficient one-pot multi-
component synthesis of 5-azaindoles and dihydropyrrolo-
ACHTUNGTREN[NUNG 3,2-c]azepines by the zirconocene-mediated coupling of sili-
À
azacycles (Figures 2 and 3). The bond length of C6 N4 in
À
8a is 1.277(7) ꢂ, whereas the bond length of C47 N7 in 9a
is 1.481(3) ꢂ. In their 13C NMR spectra, the imine C6 atom
in 8a shows a singlet at d=167.18 ppm, whereas the C47
atom in 9a appears at 79.79 ppm. Similarly, dihydropyrrolo-
con-tethered diynes, nitriles, and isocyanides. Selective for-
À
mation of mono- or bis(iminoacyl) Zr intermediates
À
through insertion of isocyanide into a Zr C bond was ach-
[3,2-c]azepine derivatives 8b and 9b could also be obtained.
ieved depending on the bulkiness of isocyanides. We suc-
cessfully isolated and characterized the Cp2Zr-containing
six-component coupled key intermediates involving one
À
The hydrolysis mechanism from the bis
mediates to dihydropyrrolo[3,2-c]azepine derivatives 8 and 9
is not yet clear (see the Supporting Information for the pro-
posed mechanisms). This one-pot synthesis of
dihydropyrrolo[3,2-c]azepine derivatives through the zirco-
nocene-mediated five-component coupling of a silicon-teth-
ACHTUNGTREN(NUNG iminoacyl) Zr inter-
AHCTUNGTRENNUNG
molecule of bisACHTUNTRGNEUNG(alkynyl)silane, two nitrile molecules and
two molecules of isocyanide, which offered direct structural
evidence to understand the mechanism of sequential inser-
ACHTUNGTRENNUNG
À
tion of isocyanides into a Zr C bond. Both of these mono-
8422
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8419 – 8426

À
Intramolecular Cyclization of Iminoacyl Zr Intermediates
FULL PAPER
À
ble for X-ray analysis were grown in THF/hexane at room temperature
for three days. 1H NMR (300 MHz, C4D8O, 25 8C): d=0.29 (s, 3H;
SiMe2), 0.39 (s, 3H; SiMe2), 0.58 (d, J=6.6 Hz, 3H; CHMe2), 0.90 (d, J
= 6.6 Hz, 3H; CHMe2), 1.10 (d, J=6.6 Hz, 3H; CHMe2), 1.31 (d, J=
7.2 Hz, 3H; CHMe2), 1.30–1.52 (m, 14H; CHMe2 +C6H11), 1.70–2.00 (m,
11H; C6H11), 2.21–2.30 (m, 1H; CHMe2), 2.78–2.87 (m, 1H; CHMe2),
5.83 (s, 5H; C5H5), 6.06 (s, 5H; C5H5), 7.08–7.40 (m, 9H; C6H5),
7.73 ppm (d, J=7.5 Hz, 1H; C6H5); 13C NMR (75.4 MHz, C4D8O, 25 8C):
d=À2.94, À1.48, 18.60, 22.20, 23.35, 24.25, 24.42, 24.76, 24.95, 25.25,
25.74, 32.16, 34.70, 35.07, 35.54, 50.90, 64.13, 68.07, 109.45, 110.31, 119.90,
124.79, 125.47, 126.30, 126.85, 127.08, 127.41, 128.07, 128.12, 132.78,
140.76, 141.16, 141.47, 143.99, 164.95, 183.63, 222.57 ppm; elemental anal-
ysis calcd (%) for C54H70N4OSiZr (4·THF): C 71.63, H 7.45, N 6.68;
found: C 71.95, H 7.81, N 6.50.
and bis(iminoacyl) Zr intermediates were found to undergo
unexpected intramolecular cyclization to afford N-contain-
ing heterocycles upon hydrolysis.
Experimental Section
General methods and materials: All reactions were conducted under a
slightly positive pressure of dry nitrogen by using standard Schlenk-line
techniques or under a nitrogen atmosphere in a glove box. The nitrogen
in the glove box was constantly circulated through a copper/molecular
sieves catalyst unit. The oxygen and moisture concentrations in the at-
mosphere of the glove box were monitored by an O2/H2O Combi-Ana-
lyzer (MBRAUN) to ensure that both were always below 1 ppm. Unless
otherwise noted, all starting materials were commercially available and
were used without further purification. Toluene was heated at reflux and
was distilled from sodium/benzophone ketyl under a nitrogen atmos-
phere. nBuLi was obtained from Kanto Chemicals. 1H and 13C NMR
spectra were recorded on a JNM-AL300 spectrometer (FT, 300 MHz for
1H; 75 MHz for 13C). Micro elemental analyses were performed on a
MICRO CORDER JM10 apparatus. Compounds 2 were prepared and
isolated by following our reported procedure.[15a,b]
À
Isolation of iminoacyl Zr intermediate 5 from silicon-tethered diyne 1a,
two molecules of iPrCN, and two molecules of 2,6-dimethylphenyl isocy-
anide: In a 20 mL Schlenk tube, 2,6-dimethylphenyl isocyanide (131 mg,
1.0 mmol) was added to a solution of compound 2a (310 mg, 0.50 mmol)
in benzene (3 mL). After the reaction mixture was stirred at room tem-
perature for 1 h, it was dried under vacuum and the residue was washed
with hexane. After filtering, the solid was dried under vacuum to precipi-
tate 5 as a yellow powder (277 mg, 0.31 mmol, 63% yield). 1H NMR
(300 MHz, C4D8O, 25 8C): d=0.49 (s, 3H; SiMe2), 0.54 (s, 3H; SiMe2),
1.04 (d, J = 7.2 Hz, 3H; CHMe2), 1.25 (d, J = 6.9 Hz, 3H; CHMe2), 1.74
(s, 3H; 2,6-Me2Ph), 1.90 (s, 3H; 2,6-Me2Ph), 2.21 (s, 3H; 2,6-Me2Ph), 2.44
(s, 3H; 2,6-Me2Ph), 2.83–2.92 (m, 1H; CHMe2), 3.07–3.16 (m, 1H;
CHMe2), 5.89 (s, 5H; C5H5), 5.92 (s, 5H; C5H5), 6.15–6.65 (m, 6H; 2,6-
Me2Ph), 7.32–7.40 (m, 8H; C6H5), 8.03 ppm (d, J = 8.1 Hz, 2H; C6H5);
13C NMR (75.4 MHz, C4D8O, 25 8C): d=À0.97, 0.10, 0.43, 18.80, 19.47,
19.68, 20.81, 20.87, 21.59, 21.85, 25.66, 32.36, 33.51, 108.48, 109.17, 116.64,
118.15, 125.34, 126.03, 126.64, 126.98, 127.07, 127.15, 126.46, 127.64,
128.24, 129.04, 129.98, 130.19, 136.58, 138.41, 138.82, 139.14, 145.54,
151.96, 154.92, 161.63, 180.93, 184.93 ppm; elemental analysis calcd (%)
for C54H58N4SiZr: C 73.50, H 6.63, N 6.35; found: C 73.66, H 6.48, N
6.50.
À
Isolation of iminoacyl Zr intermediate 3a from silicon-tethered diyne
1a, two molecules of iPrCN, and tBuNC: In a 20 mL Schlenk tube,
tBuNC (56 mL, 0.50 mmol) was added to a solution of compound 2a
(310 mg, 0.50 mmol) in benzene (3 mL) with a syringe. After the reaction
mixture was stirred at room temperature for 1 h, it was dried under
vacuum and the residue was washed with hexane. After filtering, the
solid was dried under vacuum to precipitate 3a as a yellow powder
(319 mg, 0.455 mmol, 91% yield). 1H NMR (300 MHz, C6D6, 258C): d=
0.38 (s, 3H; SiMe2), 0.91 (s, 3H; SiMe2), 1.11 (d, J=6.9 Hz, 3H; CHMe2),
1.18–1.28 (m, 15H; CHMe2 +tBu), 0.93 (d, J=6.8 Hz, 3H; CHMe2), 1.66
(d, J=6.9 Hz, 3H; CHMe2), 2.69–2.78 (m, 1H; CHMe2), 3.03–3.12 (m,
1H; CHMe2), 5.67 (s, 5H; C5H5), 5.71 (s, 5H; C5H5), 7.03–7.51 (m, 9H;
C6H5), 7.88 ppm (d, J=7.2 Hz, 1H; C6H5); 13C NMR (75.4 MHz, C6D6,
258C): d=À2.97, 1.15, 14.32, 19.35, 22.66, 26.08, 30.08, 33.17, 35.36, 54.49,
60.89, 107.22, 108.08, 120.26, 124.20, 126.14, 126.34, 127.33, 127.54, 127.92,
129.68, 132.17, 132.88, 140.15, 141.35, 144.34, 156.76, 186.88, 234.17 ppm;
elemental analysis calcd (%) for C41H49N3SiZr: C 70.03, H 7.02, N 5.98;
found: C 69.95, H 7.20, N 5.60.
À
Hydrolysis of iminoacyl Zr intermediate 3a to give 1H-pyrrolo
N
c]pyridine 6a, tBuNH2, and zirconasiloxane 7: Under a nitrogen atmos-
phere, an NMR tube fitted with a Young valve was charged with 3a
(70 mg, 0.10 mmol) and C6D6 (0.5 mL). Three equivalents of H2O
(5.4 uL, 0.30 mmol) were added to the solution with a syringe at room
temperature, and then the NMR tube was shaken immediately. The mix-
ture in the NMR tube was monitored by 1H and 13C NMR spectroscopy
and 6a was found to be the main product in more than 90% yield by
1H NMR spectroscopy. Then the mixture was filtered in the glove box
and the filtrate was subjected into GC–MS. A peak at m/z=73 that
could be assigned to the relative molecule weight of tBuNH2 was found.
The residue was washed with diethyl ether several times until it turned in
to a pale solid and was further characterized by elemental analysis to be
7.[15b]
À
Isolation of iminoacyl Zr intermediate 3b from silicon-tethered diyne
1b, two molecules of iPrCN, and tBuNC: In a 20 mL Schlenk tube,
tBuNC (56 mL, 0.50 mmol) was added to a solution of compound 2b
(324 mg, 0.50 mmol) in benzene (3 mL) with a syringe. After the reaction
mixture was stirred at room temperature for 1 h, it was dried under
vacuum and the residue was washed with hexane. After filtering, the
solid was dried under vacuum to precipitate 3b as a yellow powder
(302 mg, 0.415 mmol, 83% yield). 1H NMR (300 MHz, C4D8O, 25 8C):
d=0.20 (s, 3H; SiMe2), 0.68 (d, J=6.6 Hz, 3H; CHMe2 +SiMe2), 0.73 (d,
J=6.6 Hz, 3H; CHMe2), 1.05 (d, J=7.2 Hz, 3H; CHMe2), 1.61 (s, 9H;
tBu), 1.49 (t, J=6.9 Hz, 3H; CHMe2), 2.31 (s, 3H; CH3), 2.36–2.43 (m,
1H; CHMe2), 2.46 (s, 3H; CH3), 3.04–3.14 (m, 1H; CHMe2), 5.77 (s, 5H;
C5H5), 6.85 (s, 5H; C5H5), 7.06–7.25 (m, 7H; C6H5), 7.54 ppm (d, J=
7.5 Hz, 1H; C6H5); 13C NMR (75.4 MHz, C4D8O, 25 8C): d=À4.12,
À0.13, 18.24, 20.07, 20.47, 21.76, 21.98, 25.29, 29.68, 32.75, 34.32, 61.09,
106.92, 107.80, 119.31, 123.33, 127.40, 127.60, 128.07, 129.32, 131.66,
132.28, 134.65, 135.10, 136.85, 138.10, 143.96, 156.42, 185.50 ppm; elemen-
tal analysis calcd (%) for C43H53N3SiZr: C 70.63, H 7.31, N 5.75; found:
C 70.42, H 7.51, N 5.40.
Formation of 1H-pyrroloACTHNUTRGNEUG[N 3,2-c]pyridine 6 from one molecule of the sili-
con-tethered diyne with two nitrile molecules, and one isocyanide—A
general procedure for the formation of 6d: In a 20 mL Schlenk tube,
nBuLi (2.4 mmol, 1.6m, 1.5 mL) was added dropwise with a syringe to a
solution of Cp2ZrCl2 (1.2 mmol, 350 mg) in toluene (10 mL) at À788C
(dry ice/acetone). After the addition was complete, the reaction mixture
was stirred at À788C for 1 h. Then bis(p-tolylethynyl)dimethylsilane (1b,
1 mmol, 288 mg) was added, and the reaction mixture was warmed to
508C and stirred at this temperature for 1 h. After isobutyronitrile
(1.5 mmol, 0.135 mL) was added, the reaction mixture was stirred at this
temperature for 1 h. Then tBuNC (1.2 mmol, 100 mg, 136 mL) was added
and the reaction mixture was stirred at 508C for 1 h. The reaction mix-
ture was quenched with a saturated aqueous solution of NaHCO3. The
resulting mixture was extracted with diethyl ether (10 mLꢃ3) then
washed with water and brine. The extract was dried over anhydrous
MgSO4 and the solvent was evaporated in vacuo to give a yellow solid,
which was purified by using an SiO2 column with petroleum ether, dieth-
yl ether, and triethylamine (100:10:1) as the eluent to give product 6d.
À
Isolation of iminoacyl Zr intermediate 4 from silicon-tethered diyne 1a,
two molecules of iPrCN, and two molecules of CyNC: In a 20 mL
Schlenk tube, CyNC (124 mL, 1.0 mmol) was added to a solution of com-
pound 2a (310 mg, 0.50 mmol) in benzene (3 mL) with a syringe. After
the reaction mixture was stirred at room temperature for 1 h, it was dried
under vacuum and the residue was washed with hexane. After filtering,
the solid was dried under vacuum to precipitate 4 as a yellow powder
(326 mg, 0.39 mmol, 78% yield). Single crystals of 4·THF that were suita-
Chem. Eur. J. 2010, 16, 8419 – 8426
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8423

Z. Xi et al.
The characterization data of product 6a has been published in our previ-
The resulting mixture was extracted with diethyl ether (10 mLꢃ3) then
washed with water and brine. The extract was dried over anhydrous
MgSO4. The solvent was evaporated in vacuo to give a yellow solid,
which was purified by using a SiO2 column with petroleum ether, diethyl
ether, and triethylamine (100:7.5:1) as the eluent to give product 9a, and
with petroleum ether, diethyl ether, and triethylamine (100:15:1) as the
eluent to give product 8a. Single crystals of 8a·1.5DME suitable for X-
ray analysis were grown in 1,2-dimethoxyethane/diethyl ether at room
temperature for three days. Single crystals of 9a suitable for X-ray analy-
sis were grown in diethyl ether/hexane at room temperature for one
week.
ous communication.[15b]
2,4-Di-sec-butyl-3,7-diphenyl-1H-pyrrolo
[3,2-c]pyridine
(6b):
White
solid; isolated yield: 55% (231 mg); 1H NMR (400 MHz, CDCl3, 258C,
TMS): d=0.54–0.63 (m, 3H), 0.74–0.87 (m, 3H), 1.10–1.24 (m, 6H),
1.36–1.42 (m, 1H), 1.53–1.59 (m, 2H), 1.73–1.79 (m, 1H), 2.67–2.80 (m,
2H), 7.22–7.48 (m, 6H), 7.55 (t, J=7.6 Hz, 2H), 7.64 (d, J=7.6 Hz, 2H),
8.28 (s, 1H), 8.33 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3, 258C,
TMS): d=12.12, 12.19, 12.21, 12.24, 19.36, 19.42, 20.91, 29.43, 29.47,
29.62, 29.71, 30.28, 32.50, 32.55, 37.51, 114.85, 114.94, 118.27, 122.56,
122.58, 127.07, 127.19, 127.45, 127.64, 127.87, 127.93, 127.95, 128.13,
128.16, 128.19, 128.32, 128.52, 128.93, 129.36, 131.07, 131.12, 131.39,
131.47, 131.85, 136.15, 136.18, 136.50, 137.03, 138.59, 139.13, 141.09,
141.16, 159.18, 159.24 ppm; HRMS: m/z: calcd for C27H31N2 [M+H]+:
383.2487; found: 383.2473.
N-(2,6-Dimethylphenyl)-6-(2,6-dimethylphenylimino)-2,4-diisopropyl-3,8-
diphenyl-1,6-dihydropyrroloACHTNUTRGNEUNG[3,2-c]azepin-7-amine (8a): Colorless crys-
tals; isolated yield: 46% (278 mg); 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=0.59 (d, J=6.9 Hz, 6H; CHMe2), 1.01 (d, J=6.9 Hz, 3H;
CHMe2), 1.81 (s, 6H; Me), 2.23 (s, 6H; Me), 2.94–3.03 (m, 2H; CHMe2),
6.08 (s, 1H; NH), 6.81 (t, J=8.1 Hz, 4H; CH), 6.92 (d, J=7.2 Hz, 2H;
CH), 7.10–7.33 (m, 10H; CH), 7.44 ppm (brs, 1H; NH); 13C NMR
(75.4 MHz, CDCl3, 258C, TMS): d=17.76, 19.17, 20.73, 22.70, 24.77,
33.24, 106.65, 118.38, 118.61, 122.10, 125.27, 126.16, 127.05, 127.38, 127.80,
128.04, 128.09, 128.64, 129.72, 130.21, 134.36, 134.97, 135.18, 135.91,
136.27, 137.82, 147.28, 158.59, 167.17 ppm; HRMS: m/z: calcd for
C42H45N4 [M+H]+: 605.3644; found: 605.3678.
2,4-Dicyclohexyl-3,7-diphenyl-1H-pyrroloACTHNUTRGNE[NUG 3,2-c]pyridine (6c): White
solid; isolated yield: 66% (287 mg); m.p.: 218–2208C; 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=0.74–1.88 (m, 20H), 2.58–2.68 (m,
2H), 7.24–7.66 (m, 10H), 8.25 (s, 1H), 8.31 ppm (brs, 1H); 13C NMR
(75.4 MHz, CDCl3, 258C, TMS): d=25.79, 26.00, 26.30, 26.60, 32.21,
33.27, 35.67, 41.30, 114.13, 118.64, 122.28, 127.33, 127.88, 128.16, 128.43,
129.64, 131.38, 136.43, 136.83, 137.03, 139.36, 141.76, 159.55 ppm; HRMS:
m/z: calcd for C31H35N2 [M+H]+: 435.2800; found: 435.2780.
N-(2,6-Dimethylphenyl)-6-(2,6-dimethylphenylimino)-2,4-dicyclohexyl-3,8-
ditolyl-1,6-dihydropyrroloACTHNUGTRNEUNG[3,2-c]azepin-7-amine (8b): White solid; isolat-
2,4-Diisopropyl-3,7-di-p-tolyl-1H-pyrrolo
G
(6d):
White
solid; isolated yield: 41% (156 mg); m.p.: 181–1848C; 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=1.14 (d, J=6.9 Hz, 6H), 1.20 (d, J=
6.9 Hz, 6H), 2.44 (s, 3H), 2.45 (s, 3H), 2.95–3.13 (m, 2H), 7.24 (s, 4H),
7.36 (d, J=7.8 Hz, 2H), 7.53 (d, J=7.5 Hz, 2H), 8.25 (s, 1H), 8.32 ppm
(brs, 1H); 13C NMR (75.4 MHz, CDCl3, 258C, TMS): d=21.26, 21.35,
22.05, 22.70, 25.55, 30.61, 113.58, 118.47, 121.84, 128.08, 128.75, 130.14,
130.84, 133.03, 133.55, 136.70, 137.04, 137.56, 139.05, 142.34, 159.70 ppm;
HRMS: m/z: calcd for C27H31N2 [M+H]+: 383.2487; found: 383.2469.
ed yield: 33% (235 mg); 1H NMR (400 MHz, CDCl3, 258C, TMS): d=
0.57–0.63 (m, 2H; CH2), 0.83–0.90 (m, 3H; CH2), 1.05–1.14 (m, 4H;
CH2), 1.17–1.25 (m, 2H; CH2), 1.37–1.45 (m, 3H; CH2), 1.57–1.71 (m,
6H; CH2), 1.75 (s, 6H; Me), 1.79–1.85 (m, 1H; CH), 2.22 (s, 6H; Me),
2.31 (s, 3H; Me), 2.35 (s, 3H; Me), 2.53–5.59 (m, 1H; CH), 5.97 (s, 1H;
NH), 6.81 (t, J=7.6 Hz, 4H; CH), 6.89 (d, J=7.6 Hz, 2H; CH), 6.96 (d,
J=8.0 Hz, 2H; CH), 7.08 (q, J=7.6 Hz, 4H; CH), 7.19 (d, J=8.0 Hz,
2H; CH), 7.43 ppm (brs, 1H; NH); 13C NMR (100 MHz, CDCl3, 258C,
TMS): d=17.72, 19.15, 21.12, 21.15, 25.71, 25.96, 26.11, 26.33, 30.97,
33.27, 34.81, 43.24, 106.47, 118.49, 118.76, 121.92, 125.14, 126.94, 127.79,
128.20, 128.67, 129.00, 129.37, 129.67, 130.05, 132.88, 133.36, 133.47,
135.18, 135.24, 135.54, 135.92, 136.99, 138.06, 147.41, 158.59, 168.16 ppm;
HRMS: m/z: calcd for C50H57N4 [M+H]+: 713.4578; found: 713.4560.
2,4-Di-sec-butyl-3,7-di-p-tolyl-1H-pyrrolo
(6e):
White
solid; isolated yield: 53% (217 mg); 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=0.55–0.65 (m, 3H), 0.74–0.83 (m, 3H), 1.10–1.23 (m, 6H),
1.35–1.45 (m, 1H), 1.48–1.61 (m, 2H), 1.71–1.84 (m, 1H), 2.45 (s, 3H),
2.46 (s, 3H), 2.66–2.77 (m, 1H), 2.78–2.85 (m, 1H), 7.23 (s, 4H), 7.37 (d,
J=8.1 Hz, 2H), 7.54 (d, J=7.8 Hz, 2H), 8.22 (brs, 1H), 8.26 ppm (s,
1H); 13C NMR (75.4 MHz, CDCl3, 258C, TMS): d=12.20, 12.29, 12.35,
19.57, 19.61, 21.05, 21.07, 21.29, 21.36, 29.58, 29.74, 29.77, 29.84, 32.54,
32.58, 37.52, 114.96, 115.05, 118.38, 122.84, 128.27, 128.83, 128.87, 128.92,
130.33, 131.16, 131.24, 131.46, 131.58, 133.32, 133.86, 136.82, 137.30,
137.71, 139.37, 141.20, 141.28, 159.40 ppm; HRMS: m/z: calcd for
C29H35N2 [M+H]+: 411.2800; found: 411.2795.
N6,N7-Bis(2,6-dimethylphenyl)-2,4-diisopropyl-3,8-diphenyl-1,6-
dihydropyrroloACTHNUGRTNEUNG[3,2-c]azepine-6,7-diamine (9a): Yellow solid; isolated
yield: 24% (145 mg); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=0.80
(d, J=6.6 Hz, 3H; CHMe2), 0.88 (d, J=6.6 Hz, 3H; CHMe2), 0.99 (d, J=
6.0 Hz, 3H; CHMe2), 1.22 (d, J=6.9 Hz, 3H; CHMe2), 1.68 (s, 3H; Me),
2.35 (s, 3H; Me), 2.38–2.45 (m, 1H; CHMe2), 2.57 (s, 6H; Me), 3.02–3.09
(m, 1H; CHMe2), 4.33 (d, J=5.1 Hz, 1H; CHNH), 4.68 (d, J=5.1 Hz,
1H; CHNH), 6.39 (d, J=7.5 Hz, 1H; CH), 6.57 (t, J=7.2 Hz, 1H; CH),
6.75 (d, J=7.2 Hz, 1H; CH), 6.85–7.34 (m, 13H; CH), 7.53 (brs, 1H;
NH), 7.89 ppm (brs, 1H, NH); 13C NMR (75.4 MHz, CDCl3, 258C,
TMS): d=19.30, 19.99, 20.42, 22.28, 22.71, 23.03, 24.70, 33.04, 79.79,
101.03, 118.20, 118.97, 121.82, 123.35, 125.59, 125.83, 127.06, 127.43,
128.00, 128.55, 128.68, 128.77, 129.66, 129.72, 130.52, 130.60, 131.92,
133.62, 133.70, 136.38, 136.98, 137.04, 137.78, 147.01, 167.69 ppm; HRMS:
m/z: calcd for C42H47N4 [M+H]+: 607.3801; found: 607.3794.
2,4-Bis(1-phenylcyclopropyl)-3,7-di-p-tolyl-1H-pyrroloACTHNUTRGNE[UNG 3,2-c]pyridine
(6 f): White solid; isolated yield: 46% (487 mg); 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=0.83–1.38 (m, 8H), 2.30 (s, 3H), 2.45 (s, 3H),
6.56 (d, J=7.8 Hz, 2H), 6.64–78 (m, 4H), 6.93 (d, J=8.1 Hz, 2H), 7.01–
7.25 (m, 6H), 7.36 (d, J=7.8 Hz, 2H), 7.56 (d, J=7.8 Hz, 2H), 8.36 (s,
1H), 8.50 ppm (brs, 1H); 13C NMR (75.4 MHz, CDCl3, 258C, TMS): d=
17.79, 19.23, 21.27, 21.30, 22.19, 29.46, 117.98, 119.67, 124.11, 124.59,
125.06, 125.87, 125.95, 127.70, 127.86, 128.33, 128.56, 130.35, 131.33,
132.11, 133.23, 135.82, 138.01, 138.08, 139.40, 144.97, 145.97, 155.12 ppm;
HRMS: m/z: calcd for C39H35N2 [M+H]+: 531.2800; found: 531.2783.
N6,N7-Bis(2,6-dimethylphenyl)-2,4-dicyclohexyl-3,8-ditolyl-1,6-
dihydropyrroloACTHNUGRTNEUNG[3,2-c]azepine-6,7-diamine (9b): Yellow solid; isolated
Formation of dihydropyrroloACTHNUGRTENUNG[3,2-c]azepine 8 and 9 from one molecule of
yield: 21% (150 mg); 1H NMR (400 MHz, CDCl3, 258C, TMS): d=0.55–
0.67 (m, 1H; CH2), 0.80–0.88 (m, 1H; CH2), 0.94–1.05 (m, 5H; CH2),
1.08–1.25 (m, 2H; CH2), 1.43–1.61 (m, 9H; CH2), 1.64 (s, 3H; Me), 1.72–
1.77 (m, 1H; CH2), 1.98–2.00 (m, 2H; CH), 2.14 (s, 3H; Me), 2.32 (s,
3H; Me), 2.37 (s, 3H; Me), 2.56 (s, 3H; Me), 2.59–5.62 (m, 1H; CH),
4.27 (d, J=5.2 Hz, 1H; CHNH), 4.63 (d, J=5.2 Hz, 1H; CHNH), 6.35
(d, J=7.6 Hz, 1H; CH), 6.53 (t, J=7.6 Hz, 1H; CH), 6.62 (d, J=7.6 Hz,
1H; CH), 6.73 (t, J=8.0 Hz, 2H; CH), 6.77 (s, 2H; CH), 6.84 (t, J=
8.0 Hz, 1H; CH), 7.04 (d, J=7.6 Hz, 2H; CH), 7.11 (q, J=7.6 Hz, 4H;
CH), 7.51 (brs, 1H; NH), 7.69 ppm (brs, 1H; NH); 13C NMR (100 MHz,
CDCl3, 258C, TMS): d=19.07, 19.33, 19.98, 20.94, 21.18, 25.76, 26.23,
26.31, 26.39, 26.47, 26.86, 30.89, 32.75, 33.03, 33.69, 34.70, 43.20, 79.85,
100.99, 118.31, 119.18, 121.73, 123.06, 126.98, 127.61, 128.11, 128.27,
the silicon-tethered diyne with two molecules of iPrCN, and two mole-
cules of 2,6-dimethylphenyl isocyanides—A general procedure for the
formation of 8a and 9a: In a 50 mL Schlenk tube, nBuLi (2.4 mmol,
1.6m, 1.5 mL) was added dropwise with a syringe to a solution of
Cp2ZrCl2 (1.2 mmol, 350 mg) in toluene (20 mL) at À788C (dry ice/ace-
tone). After the addition was complete, the reaction mixture was stirred
at À788C for 1 h. Then bis(phenylethynyl)dimethylsilane (1a; 1 mmol,
260 mg) was added and the reaction mixture was warmed to 508C and
stirred at this temperature for 1 h. After isobutyronitrile (1.5 mmol,
0.135 mL) was added, the reaction mixture was stirred at this tempera-
ture for 1 h. Then 2,6-dimethylphenyl isocyanide (2.4 mmol, 314 mg) was
added and the reaction mixture was stirred at 508C for 1 h. The reaction
mixture was quenched with a saturated aqueous solution of NaHCO3.
8424
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8419 – 8426

À
Intramolecular Cyclization of Iminoacyl Zr Intermediates
FULL PAPER
12860, 128.70, 129.71, 130.26, 130.44, 131.94, 132.78, 133.07, 133.90,
134.11, 135.08, 135.19, 136.26, 137.93, 148.13, 167.01 ppm: HRMS: m/z:
calcd for C50H59N4 [M+H]+: 715.4740; found: 715.4728.
Hughes, M. Bochmann, Organometallics 2001, 20, 4080–4091;
n) P. R. Sharp, J. Am. Chem. Soc. 2000, 122, 9880–9881; o) S.
Kuroda, Y. Sato, M. Mori, J. Organomet. Chem. 2000, 611, 304–307;
p) A. AntiÇolo, F. Carrillo-Hermosilla, A. Corrochano, J. Fernꢄn-
dez-Baeza, A. Lara-Sanchez, M. R. Ribeiro, M. Lanfranchi, A.
Otero, M. A. Pellinghelli, M. F. Portela, J. V. Santos, Organometallics
2000, 19, 2837–2843; q) V. Cadierno, M. Zablocka, B. Donnadieu,
A. Igau, J. P. Majoral, A. Skowronska, J. Am. Chem. Soc. 1999, 121,
11086–11092; r) W. Ahlers, G. Erker, R. Frçhlich, J. Organomet.
Chem. 1998, 571, 83–89; s) D. Jacoby, S. Isoz, C, Floriani, A.
Chiesi-Villa, C. Rizzoli, J. Am. Chem. Soc. 1995, 117, 2805–2816;
t) B. Temme, G. Erker, R. Frçhlich, M. Grehl, Angew. Chem. 1994,
106, 1570–1572; Angew. Chem. Int. Ed. Engl. 1994, 33, 1480–1482;
u) A. S. Guram, R. F. Jordan, J. Org. Chem. 1993, 58, 5595–5597;
v) R. A. Fisher, S. L. Buchwald, Organometallics 1990, 9, 871–873.
X-ray crystallographic studies: The single crystals of 4·THF, 8a·1.5DME,
and 9a that were suitable for X-ray analysis were grown as described
above. The crystals of 4·THF were manipulated under a nitrogen atmos-
phere and were sealed in a thin-walled glass capillary tube. Data collec-
tions for 4·THF were performed at À1508C on a Rigaku RAXIS RAPID
IP diffractometer using graphite monoACTHNUTRGNEGcNU hromated MoKa radiation (l=
0.71073 ꢂ). Data collections for 8a·1.5DME and 9a were performed at
208C on a Rigaku RAXIS RAPID IP diffractometer using graphite mon-
ochromated MoKa radiation (l=0.71073 ꢂ). The determination of crystal
class and unit cell parameters was carried out by the Rapid-AUTO
(Rigaku 2000) program package. The raw frame data were processed by
using Crystal Structure (Rigaku/MSC 2000) to yield the reflection data
file. The structures of 4·THF, 8a·1.5DME, and 9a were solved by using
the SHELXTL program.[19] Refinement was performed on F2, anisotropi-
cally for all the non-hydrogen atoms by the full-matrix least-squares
method. The hydrogen atoms were placed at the calculated positions and
were included in the structure calculation without further refinement of
the parameters. Crystal data, data collection, and data processing param-
eters for compounds 4·THF, 8a·1.5DME, and 9a are summarized in the
Supporting Information. CCDC-746734 (4·THF), CCDC-765361
(8a·1.5DME), and CCDC-765360 (9a) contain the supplementary crys-
tallographic data for this paper (excluding structure factors). These data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
À
[3] For selected examples of bis(iminoacyl) Zr complexes formed by
double-insertion of isocyanides, see: a) C. Valero, M. Grehl, D.
Wingbermuehle, L. Kloppenburg, D. Carpenetti, G. Erker, J. L. Pe-
tersen, Organometallics 1994, 13, 415–417; b) F. J. Berg, J. L. Peters-
en, Tetrahedron 1992, 48, 4749–4756; c) F. J. Berg, J. L. Petersen,
Organometallics 1991, 10, 1599–1607; d) F. J. Berg, J. L. Petersen,
Organometallics 1989, 8, 2461–2470.
2
À
[4] For the [1,2]-alkyl shift of h -iminoacyl Zr complexes to form zirco-
naaziridine, see: a) R. J. Whitby, S. Dixon, P. R. Maloney, P. Dele-
rive, B. J. Goodwin, D. J. Parks, T. M. Willson, J. Med. Chem. 2006,
49, 6652–6655; b) G. D. Probert, R. J. Whitby, S. J. Coote, Tetrahe-
dron Lett. 1995, 36, 4113–4116.
[5] For the formation of diazazirconacycles by the rearrangement of h2-
À
iminoacyl Zr complexes, see: a) N. Suzuki, D. Hashizume, H. Yoshi-
da, M. Tezuka, K. Ida, S. Nagashima, T. Chihara, J. Am. Chem. Soc.
2009, 131, 2050–2051; b) M. A. Bach, T. Beweries, V. V. Burlakov, P.
Arndt, W. Baumann, A. Spannenberg, U. Rosenthal, Organometal-
lics 2007, 26, 4592–4597; c) C. Ramos, P. Royo, M. Lanfranchi,
M. A. Pellinghelli, A. Tiripicchio, Eur. J. Inorg. Chem. 2005, 3962–
3970; d) J. Cano, M. Sudupe, P. Royo, M. E. G. Mosquera, Organo-
metallics 2005, 24, 2424–2432; e) T. G. Ong, D. Wood, G. P. A. Yap,
D. S. Richeson, Organometallics 2001, 20, 1–3; f) M. J. Scott, S. J.
Lippard, Organometallics 1997, 16, 5857–5868; g) L. Giannini, A.
Caselli, E. Solari, C. Floriani, A. Chiesi-Villa, C. Rizzoli, N. Re, A.
Sgamellotti, J. Am. Chem. Soc. 1997, 119, 9709–9719; h) L. R.
Chamberlain, L. D. Durfee, P. E. Fanwick, L. M. Kobriger, S. L. La-
tesky, A. K. McMullen, B. D. Steffey, I. P. Rothwell, K. Folting, J. C.
Huffman, J. Am. Chem. Soc. 1987, 109, 6068–6076; i) S. L. Latesky,
A. K. McMullen, G. P. Niccolai, I. P. Rothwell, J. C. Huffman, Orga-
nometallics 1985, 4, 1896–1898; and by the direct reaction of isocya-
Acknowledgements
This work was supported by the National Natural Science Foundation of
China and the Major State Basic Research Development Program
(2006CB806105). The Cheung Kong Scholars Programme, Qiu Shi Sci-
ence & Technologies Foundation, Dow Corning Corporation, Eli Lilly
China, and BASF are gratefully acknowledged.
[1] For selected reviews of synthetic application of isocyanides, see:
a) A. Dçmling, Chem. Rev. 2006, 106, 17–89; b) M. Suginome, Y.
Ito, Adv. Polym. Sci. 2004, 171, 77–136; c) J. Zhu, Eur. J. Org.
Chem. 2003, 1133–1144; d) A. Dçmling, I. Ugi, Angew. Chem. 2000,
112, 3300–3344; Angew. Chem. Int. Ed. 2000, 39, 3168–3210; e) I.
Ugi, S. Lohberger, R. Karl, Comprehensive Organic Synthesis,
Vol. 2, Pergamon Press, Oxford, 1991, p. 1083.
À
nides with the Zr C bond, see: j) T. V. V. Ramakrishna, S. Lushni-
kova, P. R. Sharp, Organometallics 2002, 21, 5685–5687; k) L. Turcu-
let, T. D. Tilley, Organometallics 2002, 21, 3961–3972; see also refer-
[2] For selected examples of h2-iminoacyl–Zr complexes formed by
mono-insertion of isocyanides, see: a) P. Spies, G. Kehr, S. Kehr, R.
Frçhlich, G. Erker, Organometallics 2007, 26, 5612–5620; b) C.
Ramos, P. Royo, M. Lanfranchi, M. A. Pellinghelli, A. Tiripicchio,
Organometallics 2007, 26, 445–454; c) A. AntiÇolo, R. Fernꢄndez-
Galꢄn, A. Otero, S. Prashar, I. Rivilla, A. M. Rodrꢅguez, J. Organo-
met. Chem. 2006, 691, 2924–2932; d) L. Chen, W. L. Nie, J. Paradies,
G. Kehr, R. Frçhlich, K. Wedeking, G. Erker, Organometallics 2006,
25, 5333–5344; e) L. Deng, H. S. Chan, Z. Xie, J. Am. Chem. Soc.
2005, 127, 13774–13775; f) M. Hill, G. Erker, G. Kehr, R. Frçhlich,
O. Kataeva, J. Am. Chem. Soc. 2004, 126, 11046–11057; g) Y.
Zhang, R. J. Keaton, L. R. Sita, J. Am. Chem. Soc. 2003, 125, 8746–
8747; h) A. Sebastiꢄn, P. Royo, P. Gꢆmez-Sal, C. R. de Arellano,
Eur. J. Inorg. Chem. 2004, 3814–3821; i) R. Fischer, D. Frank, W.
Gaderbauer, C. Kayser, C. Mechtler, J. Baumgartner, C. Marschner,
Organometallics 2003, 22, 3723–3731; j) A. M. Martins, J. R. Ascen-
so, C. G. de Azevedo, A. R. Dias, M. T. Duarte, J. F. da Silva, L. F.
Veiros, S. S. Rodrigues, Organometallics 2003, 22, 4218–4228; k) A.
AntiÇolo, R. Fernꢄndez-Galꢄn, B. Gallego, A. Otero, S. Prashar,
A. M. Rodrꢅguez, Eur. J. Inorg. Chem. 2003, 2626–2632; l) M. G.
Thorn, J. Lee, P. E. Fanwick I. P. Rothwell, J. Chem. Soc. Dalton
Trans. 2002, 3398–3405; m) T. J. Woodman, M. Thornton-Pett, D. L.
ence [3].
2
À
[6] For the rearrangement of h -iminoacyl Zr complexes to form vinyl-
amidozirconium complexes, see: a) T. G. Ong, G. P. A. Yap, D. S. Ri-
cheson, Organometallics 2003, 22, 387–389; b) H. H. Karsch, G.
Grauvogl, M. Kawecki, P. Bissinger, Organometallics 1993, 12,
2757–2766; c) S. M. Beshouri, D. E. Chebi, P. E. Fanwick, I. P. Roth-
well, J. C. Huffman, Organometallics 1990, 9, 2375–2385; d) S. M.
Beshouri, P. E. Fanwick, I. P. Rothwell J. C. Huffman, Organometal-
lics 1987, 6, 891–893.
[7] For examples of one-carbon elongation by isocyanide insertion into
À
the Zr C bond to afford an alcohol, see: a) J. L. Vasse, J. Szymo-
niak, Tetrahedron Lett. 2004, 45, 6449–6451; to afford an imine, see:
b) W. Ahlers, G. Erker, R. Frçhlich, U. Peuchert, J. Organomet.
Chem. 1999, 578, 115–124; to afford an aldehyde, see: c) E.
Thomas, A. N. Kasatkin, R. J. Whitby, Tetrahedron Lett. 2006, 47,
9181–9185; d) E. Negishi, S. Ma, T. Sugihara, Y. Noda, J. Org.
Chem. 1997, 62, 1922–1923; e) M. Mori, N. Uesaka, F. Saitoh, M.
Shibasaki, J. Org. Chem. 1994, 59, 5643–5649; f) E. Negishi, D. R.
Swanson, S. R. Miller, Tetrahedron Lett. 1988, 29, 1631–1634; to
afford a nitrile, see: g) A. Fꢇrstner, O. R. Thiel, N. Kindler, B. Bart-
Chem. Eur. J. 2010, 16, 8419 – 8426
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8425

Z. Xi et al.
kowska, J. Org. Chem. 2000, 65, 7990–7995; h) S. L. Buchwald, S. J.
LaMaire, Tetrahedron Lett. 1987, 28, 295–298.
[16] For recent reviews on multicomponent synthesis, see: a) P. Wipf, C.
Kendall, Chem. Eur. J. 2002, 8, 1779–1784; b) G. Balme, E. Bos-
sharth, N. Monteiro, Eur. J. Org. Chem. 2003, 4101–4111; c) A. Jaco-
bi von Wangelin, H. Neumann, D. Gordes, S. Klaus, D. Strubing, M.
Beller, Chem. Eur. J. 2003, 9, 4286–4294; d) Multicomponent Reac-
tions (Eds.: J. Zhu, H. Bienayme), Wiley-VCH, Weinheim, 2005.
[17] For examples of metal-mediated intramolecular reactions of silicon-
tethered diynes, see: a) Q. Luo, L. Gu, C. Wang, J. Liu, W. X.
Zhang, Z. Xi, Tetrahedron Lett. 2009, 50, 3213–3215; b) G. Dierker,
J. Ugolotti, G. Kehr, R. Frçhlich, G. Erker, Adv. Synth. Catal. 2009,
351, 1080–1088; c) J. Liu, S. Zhang, W. X. Zhang, Z. Xi, Organome-
tallics 2009, 28, 413–417; d) M. Zirngast, C. Marschner, J. Baumgart-
ner, Organometallics 2008, 27, 2570–2583; e) C. K. Jin, T. Yamada,
S. Sano, M. Shiro, Y. Nagao, Tetrahedron Lett. 2007, 48, 3671–3675;
f) J. Liu, W. X. Zhang, X. Guo, Z. Hou, Z. Xi, Organometallics
2007, 26, 6812–6820; g) J. Liu, X. Sun, M. Miyazaki, L. Liu, C.
Wang, Z. Xi, J. Org. Chem. 2007, 72, 3137–3140; h) D. Yan, J. Mohs-
seni-Ala, N. Auner, M. Bolte, J. W. Bats, Chem. Eur. J. 2007, 13,
7204–7214; i) T. Yu, X. Sun, C. Wang, L. Deng, Z. Xi, Chem. Eur. J.
[8] For the formation of exo-cyclic imines from zirconacycles with iso-
cyanides, see: a) S. Ren, H. S. Chan, Z. Xie, J. Am. Chem. Soc. 2009,
131, 3862–3863; b) M. Zablocka, M. Koprowski, B. Donnadieu, J. P.
Majoral, M. Achard, G. Buono, Tetrahedron Lett. 2003, 44, 2413–
2415; c) T. Takahashi, F. Y. Tsai, Y. Li, K. Nakajima, Organometal-
lics 2001, 20, 4122–4125.
[9] For recent reviews on azaindoles, see: a) J. J. Song, J. T. Reeves, F.
Gallou, Z. Tan, N. K. Yee, C. H. Senanayake, Chem. Soc. Rev. 2007,
36, 1120–1132; b) F. Popowycz, J. Y. Merour, B. Joseph, Tetrahedron
2007, 63, 8689–8707.
[10] For recent reviews on 7-azaindoles, see: a) J.-Y. Merour, B. Joseph,
Curr. Org. Chem. 2001, 5, 471–506; b) F. Popowycz, S. Routier, B.
Joseph, J.-Y. Merour, Tetrahedron 2007, 63, 1031–1067.
[11] For recent papers on pharmaceutical application of 5-azaindole de-
rivatives, see: a) M. Lefoix, G. Coudert, S. Routier, B. Pfeiffer, D. H.
Caignard, J. Hickman, A. Pierrꢈ, R. M. Golsteyn, S. Lꢈonce, C. Bos-
sard, J. Y. Mꢈrour, Bioorg. Med. Chem. 2008, 16, 5303–5321; b) H.
Hu, A. Kolesnikov, J. R. Riggs, K. E. Wesson, R. Stephens, E. M.
Leahy, W. D. Shrader, P. A. Sprengeler, M. J. Green, E. Sanford, M.
Nguyen, E. Gjerstad, R. Cabuslay, W. B. Young, Bioorg. Med.
Chem. Lett. 2006, 16, 4567–4570; c) J. R. Riggs, H. Hu, A. Kolesni-
kov, E. M. Leahy, K. E. Wesson, W. D. Shrader, D. Vijaykumar,
T. A. Wahl, Z. Tong, P. A. Sprengeler, M. J. Green, C. Yu, B. A.
Katz, E. Sanford, M. Nguyen, R. Cabuslay, W. B. Young, Bioorg.
Med. Chem. Lett. 2006, 16, 3197–3200.
[12] For reviews on seven-membered N-containing heterocycles, see:
a) T. M. V. D. Pinho e Melo, Eur. J. Org. Chem. 2006, 2873–2888;
b) M. D. Surman, R. H. Hutchings in Science of Synthesis (Ed.: S. M.
Weinreb), Thieme, Stuttgart, 2004, pp. 749–823; c) J.-P. K. Meigh in
Science of Synthesis (Ed.: S. M. Weinreb), Thieme, Stuttgart, 2004,
pp. 825–927; d) R. K. Smalley in Methods of Organic Chemistry
(Houben–Weyl) (Ed.: E. Schaumann), Thieme, Stuttgart, 1998,
pp. 108–199; e) R. K. Smalley in Methods of Organic Chemistry
(Houben–Weyl) (Ed.: E. Schaumann), Thieme, Stuttgart, 1998,
pp. 207–292; f) R. K. Smalley in Comprehensive Heterocyclic
Chemistry (Ed.: W. Lwowski), Pergamon Press, Bristol, 1984,
pp. 491–545.
ˇ
ˇ
ˇ
2005, 11, 1895–1902; j) M. Horꢄcek, P. Stepnicka, R. Gyepes, I. Cꢅs-
ˇ
ˇ
ˇ
arovꢄ, J. Kubista, L. Lukesovꢄ, P. Meunier, K. Mach, Organometal-
lics 2005, 24, 6094–6103; k) T. Yu, L. Deng, C. Zhao, Z. Li, Z. Xi,
ˇ
Tetrahedron Lett. 2003, 44, 677–679; l) M. Horꢄcek, N. Bazyakina,
ˇ
ˇ
ˇ
P. Stepnicka, R. Gyepes, I. Cꢅsarovꢄ, S. Bredeau, P. Meunier, J. Ku-
ˇ
bista, K. Mach, J. Organomet. Chem. 2001, 628, 30–38; m) P.-M.
Pellny, N. Peulecke, V. V. Burlakov, W. Baumann, A. Spannenberg,
U. Rosenthal, Organometallics 2000, 19, 1198–1200; n) N. Avarvari,
N. Mꢈzailles, L. Ricard, P. Le Floch, F. Mathey, Science 1998, 280,
1587–1589; o) Z. Xi, R. Fischer, R. Hara, W. Sun, Y. Obora, N.
Suzuki, K. Nakajima, T. Takahashi, J. Am. Chem. Soc. 1997, 119,
12842–12848; p) T. Takahashi, Z. Xi, Y. Obora, N. Suzuki, J. Am.
Chem. Soc. 1995, 117, 2665–2666; q) K. Tamao, S. Yamaguchi, M.
Shiro, J. Am. Chem. Soc. 1994, 116, 11715–11722.
[18] For the formation of azazirconacycles, see: a) X. Fu, J. Chen, G. Li,
Y. Liu, Angew. Chem. 2009, 121, 5608–5612; Angew. Chem. Int. Ed.
2009, 48, 5500–5504; b) Y. Liu, B. Yan, Organometallics 2006, 25,
544–547; c) S. Zhou, D. Liu, Y. Liu, Organometallics 2004, 23,
5900–5902; d) T. Takahashi, F.-Y Tsai, Y. Li, H. Wang, Y. Kondo,
M. Yamanaka, K. Nakajima, M. Kotora, J. Am. Chem. Soc. 2002,
124, 5059–5067; e) A. A. Aziz Quntar, A. Melman, M. Srebnik, J.
Org. Chem. 2002, 67, 3769–3772; f) M. Nakamoto, T. D. Tilley, Or-
ganometallics 2001, 20, 5515–5517; g) J. A. Tunge, C. J. Czerwinski,
D. A. Gately, J. R. Norton, Organometallics 2001, 20, 254–260; h) T.
Takahashi, F.-Y. Tsai, M. Kotora, J. Am. Chem. Soc. 2000, 122,
4994–4995; i) V. Cadierno, M. Zablocka, B. Donnadieu, A. Igau, J.-
P. Majoral, Angew. Chem. 2000, 112, 4698–4702; Angew. Chem. Int.
Ed. 2000, 39, 4524–4528; j) T. Takahashi, C. Xi, Z. Xi, M. Kageya-
ma, R. Fischer, K. Nakajima, E. Negishi, J. Org. Chem. 1998, 63,
6802–6806; k) T. Zippel, P. Arndt, A. Ohff, A. Spannenberg, R.
Kempe, U. Rosenthal, Organometallics 1998, 17, 4429–4437; l) P.
Binger, F. Sandmeyer, C. Kruger, Organometallics 1995, 14, 2969–
2976; m) T. Takahashi, M. Kageyama, V. Denisov, R. Hara, E. Ne-
gishi, Tetrahedron Lett. 1993, 34, 687–690; n) E. Negishi, S. J.
Holms, J. M. Tour, J. A. Miller, F. E. Cederbaum, D. R. Swanson, T.
Takahashi, J. Am. Chem. Soc. 1989, 111, 3336–3346.
[13] a) R. K. Smalley in Comprehensive Heterocyclic Chemistry (Ed.: W.
Lwowski), Pergamon Press, Bristol, 1984, pp. 545–546; b) J.-P. K.
Meigh in Science of Synthesis (Ed.: S. M. Weinreb), Thieme, Stutt-
gart, 2004, pp. 829–830.
[14] For selected examples on synthesis of analogues of dihydropyrrolo-
ACHTUNGTRENNUNG[3,2-c]azepine, see: a) R. Martꢅnez, M. M. Arzate, M. T. Ramꢅrez-
Apan, Bioorg. Med. Chem. 2009, 17, 1849–1856; b) L. Piras, E.
Genesio, C. Ghiron, M. Taddei, Eur. J. Org. Chem. 2008, 2789–
2800; c) R. Grigg, V. Sridharan, D. A. Sykes, Tetrahedron 2008, 64,
8952–8962; d) S. Beaumont, P. Retailleau, P. Dauban, R. H. Dodd,
Eur. J. Org. Chem. 2008, 5162–5175; e) A. Putey, L. Joucla, L.
Picot, T. Bessonb, B. Joseph, Tetrahedron 2007, 63, 867–879; f) R.
Martꢅnez, J. G. ꢉvila, M. T. Ramꢅrez-Apan, A. Pꢈrez, ꢉ. Martꢅnez,
Bioorg. Med. Chem. 2006, 14, 4007–4016; g) M.-L. Bennasar, E. Zu-
laica, S. Alonso, Tetrahedron Lett. 2005, 46, 7881–7884; h) L. Joucla,
A. Putey, B. Joseph, Tetrahedron Lett. 2005, 46, 8177–8179; i) M.
˝
Nyerges, A. Pintꢈr, A. Virꢄnyi, I. Bitter, L. Toke, Tetrahedron Lett.
2005, 46, 377–380.
[19] SHELTL 5.10 for Windows NT, Structure Determination Software
Programs, G. M. Sheldrick, Brucker Analytical X-ray Systems, Mad-
ison WI, 1997.
[15] a) S. Zhang, X. Sun, W. X. Zhang, Z. Xi, Chem. Eur. J. 2009, 15,
12608–12617; b) W. X. Zhang, S. Zhang, X. Sun, M. Nishiura, Z.
Hou, Z. Xi, Angew. Chem. 2009, 121, 7363–7367; Angew. Chem. Int.
Ed. 2009, 48, 7227–7231; c) X. Sun, C. Wang, Z. Li, S. Zhang, Z. Xi,
J. Am. Chem. Soc. 2004, 126, 7172–7173.
Received: March 19, 2010
Published online: June 11, 2010
8426
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8419 – 8426