Zirconium- and silicon-containing intermediates with three fused rings in a zirconocene-mediated intermolecular coupling reaction

Full text of DOI:10.1002/anie.200903329

Angewandte
Chemie
DOI: 10.1002/anie.200903329
Reaction Mechanisms
Zirconium- and Silicon-Containing Intermediates with Three Fused
Rings in a Zirconocene-Mediated Intermolecular Coupling Reaction**
Wen-Xiong Zhang, Shaoguang Zhang, Xiaohua Sun, Masayoshi Nishiura, Zhaomin Hou,* and
Zhenfeng Xi*
À
The isolation and reactivity of important intermediates in
transition-metal-mediated reactions are of interest in both
organometallic and synthetic organic chemistry. Studies of
these intermediates not only play an important role in the in-
depth understanding of seemingly complicated reaction
mechanisms, but can also lead to the discovery of new
synthetically useful reactions. We have reported a zircono-
cene-mediated intermolecular coupling reaction of one
molecule of a silyl-tethered diyne with three molecules of
organonitriles, which afforded pyrrolo[3,2-c]pyridine deriva-
tives (5-azaindoles) upon hydrolysis of the reaction mixture
[Eq. (1)].[1,2]
bonds and Si C bonds.[4] Complicated reactive intermediates
were found to be formed by surprising mechanisms. Syntheti-
cally useful applications of these reactive intermediates were
also achieved based on deep understanding of the reaction
mechanism.
The first reaction step between [Cp2ZrBu2][5] and 1a, as
previously reported by Takahashi and co-workers,[6] generates
a
zirconacyclobutene–silacyclobutene fused complex 3a
(Scheme 1).[6,7] To investigate the reaction mechanism in a
The most interesting feature of this above one-pot
reaction is that five components are involved and integrated
in a perfect selective manner via an unknown pathway, which
tempted us to investigate what is really going on.[3] We
anticipated that novel and important reaction patterns might
be involved. Indeed, we have now finally discovered that the
process that combines all the five components together is very
unusual, unpredictable, and of general importance to metal-
Scheme 1. Formation of zirconocene-containing intermediate 4a and
its reaction with water.
ꢀ
mediated reactions involving the cleavage of C N triple
pure and controllable system, we prepared and successfully
isolated the intermediate 3a in 93% yield by a modified
procedure.[8] Then, 3.5 molar equivalents of iPrCN was added
to a toluene solution of 3a. After the reaction mixture was
stirred at 508C for 1 h, a red powder was isolated in 90%
yield, which was confirmed to be the unexpected complex 4a
(Scheme 1).
Single crystals of 4a suitable for X-ray analysis were
grown in benzene at room temperature. X-ray analysis of 4a
(Figure 1) reveals that it consists of three fused rings: one six-
membered ring containing silicon and nitrogen, one five-
membered pyrrolo ring, and one six-membered zircona-
cycle.[9] The zirconium center is bonded to two cylcopenta-
dienyl (Cp) rings, one imine nitrogen atom, and one nitrogen
of the pyrrolo ring. The silicon atom is bonded to one
quaternary carbon atom, one imine nitrogen atom, and two
methyl groups. Two imine carbon atoms neighboring the
silicon and zirconium atoms in 4a result in a singlet at d =
[*] Dr. M. Nishiura, Prof. Dr. Z. Hou
Organometallic Chemistry Laboratory, RIKEN Advanced Science
Institute
Hirosawa 2-1, Wako, Saitama 351-0198 (Japan)
E-mail: houz@riken.jp
Prof. Dr. W.-X. Zhang, S. Zhang, Dr. X. Sun, 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)
Fax: (+86)10-6275-9728
E-mail: zfxi@pku.edu.cn
[**] This work was supported by the Natural Science Foundation of
China and the Major State Basic Research Development Program
(2006CB806105). Cheung Kong Scholars Programme, Qiu Shi
Science & Technologies Foundation, BASF, Dow Corning Corpo-
ration, and Eli Lilly China are gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903329.
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than phenyl groups for this purpose. As was the case for the
isolation of 3a, we were successful in isolation and character-
ization of the intermediate 3b, which forms orange crystalline
solids in 95% yield of isolated product.[8] A green solid 6b was
formed in 70% yield by the reaction of 3b with 1.5 equiv of
iPrCN at 508C for 1 h (Scheme 2). Although single crystals of
Figure 1. ORTEP of 4a with ellipsoids set at 30% probability; hydro-
Scheme 2. Formation of 6b and its reaction with water.
gen atoms are omitted for clarity. Selected bond lengths [ꢀ]: Zr1–N1
1.953(6), Zr1–N2 2.205(5), Si1–N3 1.752(8), Si1–C5 1.854(14), C1–
C2 1.367(9), C2–C3 1.426(8), C3–C4 1.375(8), C3–C19 1.438(9), C4–
C5 1.516(9), C5–C6 1.523(9), N1–C6 1.240(8), N3–C19 1.376(14).
6b suitable for X-ray crystallographic analysis were not
1
obtained, its H and 13C NMR data were rather informative
for the elucidation of the structure. The imine carbon atoms in
6b gave rise to a singlet at d = 181.5 ppm, and the quaternary
carbon atom linked by the zirconium and the silicon atom led
to a singlet at d = 80.9 ppm in the 13C NMR spectrum in
[D6]benzene. Hydrolysis of 6b with 1–3 equiv of H2O gave the
compound 7 in 80% yield after short-column chromatogra-
phy. The cyclic zirconasiloxane 5 was also obtained in 45%
yield of isolated product (the maximum yield is 50%).
Formation of 7 in this hydrolysis process strongly supported
a tricyclic structure of 6b consisting of one six-membered ring
containing silicon and nitrogen, one five-membered pyrrolo
ring, and one four-membered zirconacycle bearing a reactive
quaternary carbon center.
183.9 and 188.2 ppm in the 13C NMR spectrum in
[D6]benzene, and the quaternary carbon atom neighboring
the silicon atom gives rise to a singlet at d = 60.6 ppm.
Hydrolysis of 4a, after isolation, with 1–3 equiv of water
afforded the corresponding pyrrolo[3,2-c]pyridine derivative
2a in quantitative yield. Along with 2a, formation of NH3 in
the reaction solution was detected using in-situ 1H NMR
spectra. Furthermore, the whereabouts of the {Cp2Zr} and the
Me2Si moieties was determined by successful isolation of the
cyclic zirconasiloxane 5, which was obtained in 45% yield of
isolated product (the maximum yield is 50%). Compound 5
formed crystals suitable for X-ray structural analysis
(Figure 2).[9]
We propose a reaction mechanism for the formation of
To understand the reaction mechanism, one more impor-
tant question still remained. How is 4a formed from the
reaction of 3a with iPrCN? To obtain intermediates in
between, we decreased the amount of iPrCN to 1.5 equiv. We
found after several trials that the tolyl substituent was better
pyrrolo[3,2-c]pyridine based on all of the above experimental
results (Scheme 3).[10] Insertion of the C N triple bond of the
ꢀ
1
À
first organonitrile R CN into one of the Zr C bonds of 3
would afford the intermediate 8, which might immediately
ꢀ
undergo insertion of the C N triple bond of the second
2
À
organonitrile R CN into one of the Si C bonds to afford 9.
This intermediate 9 is thermodynamically unstable and would
undergo skeletal rearrangement by a 1,2-shift of the {Cp2Zr}
moiety in the azazirconacyclic ring to afford the key
intermediate 6, which is stable enough at room temperature
and could be characterized by 1H and 13C NMR. Although the
proposed intermediates 8 and 9 could not be characterized
À
owing to the fast insertion of the C ꢀ N bonds to both Zr C
À
and Si C bonds and the skeletal rearrangement, the insertion
ꢀ
À
[17]
chemistry of the C N triple bond of organonitriles into Zr C
bonds to afford azazirconacycles[11–16] and into Si C bonds
À
ꢀ
has been documented. Insertion of the C N triple bond of the
third organonitrile R CN to the Zr C bond in 6 would lead to
3
À
the formation of 4.
A proposed hydrolysis process of 4 that rationalizes the
formation of NH3, 2, and 5 is also shown in Scheme 3 (see
Supporting Information for more details). Intermediate 10
Figure 2. ORTEP of 5 with ellipsoids set at 30% probability; hydrogen
atoms are omitted for clarity. Selected bond lengths [ꢀ]: Zr1–O1
1.9632(19), Zr1–O2 1.965(2), Si1–O2 1.612(2). Symmetry-equivalent
atoms (’) are given by Àx+1, Ày, Àz+1.
À
might be formed by cleavage of the Zr N (imine) bond in 4 by
the first molecule of water. Intermediate 10 can then undergo
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Scheme 3. A proposed reaction mechanism involving one silicon-
atom-tethered diyne and three organonitriles.
Scheme 4. Further applications of intermediate 6a.
further hydrolysis with two molecules of water to afford the
diimine 11 along with loss of 5, which is formed through
coupling of Me2SiOH and Cp2ZrOH molecules. The final
product 2 was generated by the cyclization of the diimine 11
along with loss of NH3. Such a diimine cyclization producing a
pyridine ring has been reported.[11]
From the proposed reaction mechanism, we expected that
the intermediate 6 could be reacted further. Therefore, a wide
variety of substrates, such as isocyanides, formamides, acid
chlorides, aldehydes, carbon monoxide, and alkynes, were
used in place of R3CN in a one-pot process. Although carbon
monoxide and alkynes (including diphenylacetylene, DMAD,
and 4-octyne) do not show useful reactivity, many other
substrates, such as isocyanides, formamides, acid chlorides,
and aldehydes, did undergo interesting reactions and resulted
in synthetically useful methods for more diversified structures
of N-containing compounds. Representative applications of
intermediate 6a are summarized in Scheme 4.
above one-pot process (Scheme 4d), azaindole 12 was
surprisingly obtained in 70% yield upon hydrolysis with
saturated aqueous NaHCO3. When hydrolyzed with D2O
instead of saturated aqueous NaHCO3, 12 was again obtained
in a similar yield; the deuterium-labeled product 13 was not
formed. We then used Me2NCDO instead of Me2NCHO;
hydrolysis of the reaction mixture with aqueous NaHCO3
afforded the deuterated product 13 in 68% yield with D >
98% (Scheme 4e). These results indicate that the CH or CD
moiety of the carbonyl groups in formamides (-NHCHO/-
NHCDO) is incorporated into the product. Other moieties in
formamides were absent. When 6a was treated with heptanal,
formation of a new type of pyrrole derivative 15 was observed
as a mixture of two isomers (Scheme 4 f).
For all those above successful applications of intermediate
À
A new type of pyrrolo[3,2-c]pyridine derivative 12 having
a hydrogen at position 6 was obtained upon hydrolysis with
saturated aqueous NaHCO3 (Scheme 4a). It is noteworthy
6a, insertion of the unsaturated substrates into the Zr C bond
in 6a leading to the formation of 4 (in the case of isocyanide,
1,1-insertion would lead to 4’) is most likely [Eq. (2)], and has
been demonstrated in the reaction of 6a with formamide
Me2NCHO. The key intermediate 4b thus formed (yield of
isolated product 86% as brown crystals) was characterized by
X-ray single crystal structural analysis (See Supporting
À
that only one carbon atom from C ꢀ N R was integrated into
the newly formed carbon–hydrogen bond. The hydrogen
atom originated from the hydrolysis process, because deuter-
olysis of the reaction mixture with D2O could afford the
deuterium-labeled product 13 (Scheme 4b). Reaction of the
acid chloride EtCOCl with 6a generated in situ provided its
corresponding azaindole 14 in 58% yield of isolated product
(Scheme 4c). When a formamide Me2NCHO was used in the
Information),[9] which clearly shows the C O double bond
of the formamide being inserted into the Zr C bond of 6a.
Hydrolysis of 4b with aqueous NaHCO3 gave azaindole 12 in
=
À
a quantitative yield.
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In summary, the isolation and structural information of
1
in toluene, and characterized by H and 13C NMR spectroscopy
three key Zr/Si-containing intermediates 4a, 4b, and 6b were
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[9] CCDC 652444
(4a),
CCDC 733672
(4b·THF),
and
CCDC 656017 (5) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif. For crystal data of 4a, 4b, and
5, see the Supporting Information.
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Received: June 19, 2009
Published online: August 27, 2009
Keywords: azaindoles · fused-ring systems · insertion ·
.
metallocenes · zirconium
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