Unusual regioselectivity in the aldehyde addition reactions of allenyl/propargyl zirconium complexes derived from γ-(2-Pyridyl)propargyl ethers: Synthesis of multisubstituted α-hydroxyallenes

Article abstract of DOI:10.1021/om301007z

Zirconium-mediated reactions of γ-(2-pyridyl)propargyl ethers with aldehydes afford α-hydroxyallenes selectively via the formation of allenyl/propargyl zirconium species. The reaction outcome is quite different to that of the reactions using propargylic ethers without a pyridyl group reported so far, in which homopropargyl alcohols were formed predominantly. The structure of allenylzirconium intermediate has been confirmed by X-ray crystal analysis which reveals an intramolecular Zr-N coordination. DFT calculations suggest that the smaller steric effect of the pyridine ring compared with the phenyl ring and its capability to form hydrogen bondings with hydrogen atoms of the Cp ligand and the aldehyde may account for the observed regioselectivity.

Full text of DOI:10.1021/om301007z

Article
pubs.acs.org/Organometallics
Unusual Regioselectivity in the Aldehyde Addition Reactions of
Allenyl/Propargyl Zirconium Complexes Derived from γ‑(2-
Pyridyl)propargyl Ethers: Synthesis of Multisubstituted
α‑Hydroxyallenes
Guoqin Fan, Xin Xie, Yuanhong Liu,* and Yuxue Li*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, People’s Republic of China
S
* Supporting Information
ABSTRACT: Zirconium-mediated reactions of γ-(2-pyridyl)-
propargyl ethers with aldehydes afford α-hydroxyallenes
selectively via the formation of allenyl/propargyl zirconium
species. The reaction outcome is quite different to that of the
reactions using propargylic ethers without a pyridyl group
reported so far, in which homopropargyl alcohols were formed
predominantly. The structure of allenylzirconium intermediate
has been confirmed by X-ray crystal analysis which reveals an intramolecular Zr−N coordination. DFT calculations suggest that
the smaller steric effect of the pyridine ring compared with the phenyl ring and its capability to form hydrogen bondings with
hydrogen atoms of the Cp ligand and the aldehyde may account for the observed regioselectivity.
Scheme 1
INTRODUCTION
■
Allenyl/propargyl metal complexes represent one of the most
important classes of organometallics that can serve as useful
intermediates in organic synthesis, for example, in the synthesis
of highly complex molecules with biological and pharmaceutical
interest.1 However, due to the presence of the equilibrium
between allenyl and propargyl metal species, regioselectivity
control toward further C−C bond formation reactions is still an
important issue.2 Reaction of low-valent Group 4 metal
complexes (M = Zr, Ti) with propargyl alcohol derivatives
such as propargyl ethers, halides or carboxylates is a particularly
attractive protocol for the generation of allenyl/propargyl metal
species3−5 via β-heteroatom elimination reactions.3 The
reactions of these allenyl/propargyl metals with electrophiles
such as aldehydes could afford, in principle, two types of
products, homopropargyl alcohols and α-hydroxyallenes.3
Regioselectivity in these reactions depends mainly on the
nature of the metal source and the substitution patterns of the
propargylic precursors. It is generally accepted that these
reactions proceed through a SE2′ process involving a chelate
transition state as depicted in Scheme 1.3b−g,4 That means, an
allenyl metal give homopropargyl alcohols, while a propargyl
metal produces the allene products. The reactions of allenyl/
propargyl zirconium or titanium complexes with aldehydes
usually afford homopropargyl alcohols as the major products
(Scheme 2, eq 1), while the selective formation of α-
hydroxyallenes is quite rare.3f,g,4b,c For example, Sato et al.
reported that titanium-mediated reactions of propargyl
bromides with aldehydes or ketones could afford α-hydrox-
yallenes as major products. However, only propargyl bromides
bearing two hydrogen substituents at the propargyl position
Scheme 2
were successfully transformed into allenes.3f They have also
shown that propargyltitanium could be selectively formed via
reactions of the Ti(OiPr)4/2 iPrMgCl reagent with 1-
alkynylcyclopropyl carbonate, which underwent further reac-
Received: October 26, 2012
Published: February 22, 2013
© 2013 American Chemical Society
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tions with aldehydes to afford allene products.3g Hoppe et al.
developed an asymmetric synthesis of 4-hydroxyallenyl
carbamates involving the formation of propargyltitanium
species generated by asymmetric deprotonation of prochiral
propargyl carbamates followed by transmetalation.4b,c Again,
this reaction is restricted to the substrates of propargyl
carbamates derived from primary alcohols. Recently, we
reported a selective generation of the allenylzirconium
complexes and their coupling reactions with aryl halides.6
The preferential formation of the allenylzirconium species can
be explained by the steric effects since it is less congested than
the corresponding propargyl metal. Theoretical calculations
also indicated that the large repulsion between the substituents
at the propargylic position and the Cp rings decreases the
interaction of the carbanion and the metal center, thus
disfavoring the formation of propargylzirconium.6 During our
further investigations toward the nucleophilic addition reactions
of allenylzirconium with aldehydes, we found that the use of a
propargyl ether contains a pyridyl group on the alkyne terminus
can dramatically change the regioselectivity (Scheme 2, eq 2).
In this paper, we report a highly regioselective route for the
synthesis of α-hydroxyallenes via α-addition of aldehydes to (2-
pyridyl)-substituted allenylzirconium species. It is noted that
there is no report for the formation of α-hydroxyallenes with
high selectivities mediated by zirconium.
Table 1. Formation of Allenes by the Reaction of Cp2ZrBu2
with Propargyl Ethers
a
RESULTS AND DISCUSSION
Isolated yields. Unless noted, all the reactions were carried out using
■
1.6 equiv of Negishi reagent in toluene at room temperature for 3 h.
The yields obtained by using THF as solvent are shown in
parentheses. 1.25 equiv of Negishi reagent was used. 1.1 equiv of
Negishi reagent was used.
Formation of Allenes through the Reactions of
Cp2ZrBu2 with γ-(2-Pyridyl)propargyl Ethers. We envi-
sioned that the existence of a functional group containing
heteroatom like 2-pyridyl may also shift the equilibrium in favor
of the allenylzirconium species due to its strong coordination
ability with the metal, and highly regioselective reactions of
these intermediates toward electrophiles are expected.7 We
then synthesized a series of γ-(2-pyridyl)propargyl methyl or
silyl ethers 1. The reaction of 1a (R1, R2 = -(CH2)5-) with
Negishi reagent “Cp2ZrBu2” in toluene was examined first. It
was found that allene 3a was formed in 78% yield as a sole
product after hydrolysis (Table 1, entry 1). The reaction was
suggested to be initiated by coordination of “Cp2Zr” with
propargyl ether to form zirconacyclopropene, which is followed
by β-methoxide elimination to afford allenylzirconium 2. The
hydrolysis results also indicated that an allenylzirconium 2 was
formed as a major zirconium intermediate. The typical results
for allene 3 formation are shown in Table 1. It is noted that the
reaction could also be performed in THF (the results are
shown in the parentheses). Tertiary or secondary propargyl
ether having alkyl or aryl substitutents on the propargylic
position are suitable substrates (entries 1−5); however,
secondary ether afforded lower yield in toluene than that in
THF (entry 4). Primary substrate 1f is also compatible for this
reaction, furnishing terminal allene 3f in 61% yield (entry 6).
Zirconium-mediated Reactions of γ-(2-Pyridyl)-
propargyl Ethers with Aldehydes: Formation of α-
Hydroxyallenes. Next we proceeded to examine the reactions
with aldehydes in toluene. To our surprise, the reactions
proceeded readily to provide the α-hydroxyallenes 4, and there
is no apparent formation of homopropargyl alcohols (Table 2).
It should be noted that these addition reactions could not
proceed well in THF. The regioselectivity observed in this
study is in sharp contrast to the previously reported results of
allenyl zirconium or titanium complexes bearing aryl, alkyl or
TMS substituent on the α-position, in which homopropargyl
b
c
alcohol was formed predominantly through a SE2′ process.3a−e
Typical results are shown in Table 2. The reaction could be
applied to a wide range of aromatic aldehydes bearing electron-
withdrawing or electron-donating groups. The functionalities
such as −NO2, −CN, −CF3, −OMe are well tolerated during
the reaction. A thienyl aldehyde could also be used in this
reaction, and the corresponding allene 4g was formed in 62%
yield (Table 2, entry 7). For the secondary ethers 1d and 1e,
changing the solvent from THF to toluene before addition of
aldehyde was necessary to achieve the satisfied yields (entries
11−12). However, when aliphatic aldehyde was used, the
desired product 4m was obtained in low yield (entry 13). The
structure of hydroxyallenes was confirmed by X-ray single-
crystal analysis of 4a.8 It should be noted that, in all cases, we
could observe the formation of some side-products, which was
not stable upon standing at room temperature. For example, in
the case of Table 1, entry 1, 32% of these byproducts were
isolated. The NMR indicated that it contains a mixture of two
isomers without incorporation of a pyridine ring. According to
NMR results, the side-products were defined as a mixture of (4-
chlorophenyl)-(cyclopenta-1,3-dienyl)methanol and (4-
chlorophenyl)(cyclopenta-1,4-dienyl)methanol derived by at-
tack of Cp ligands to aldehydes. The participation of the Cp
ligands in various type of reactions have been reported for Zr,
Ti and Co cyclopentadienyl complexes.9 In order to understand
the effect of the 2-pyridyl group, we also synthesized a phenyl-
substituted propargyl ether 5 to probe the reaction with
aldehydes (Scheme 3). As expected, a homopropargyl alcohol 6
was obtained exclusively. The result also provided a circum-
stantial evidence for the directing effect of the 2-pyridyl group.
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Table 2. Zirconium Mediated Reactions of γ-(2-
Pyridyl)propargyl Ethers with Aldehydes
Figure 1. ORTEP drawing of complex 2a′. Selected bond lengths (Å)
and angles (deg): Zr1−N1 2.379(1), Zr1−Cl1 2.563 Zr1−C16
2.368(1), C15−C16 1.458(2), C16−C17 1.301(2), C17−C18
1.313(2), C16−Zr1−C5 87.76(5) C16−Zr1−N1 57.28(4), C15−
C16−Zr1 96.06(8), C16−C17−C18 174.60(15), C15−N1−Zr1
98.63(8), N1−C15−C16 107.90(11).
Scheme 4
geometrical centers of both Cp rings and Zr center is 128.4°.
The Zr−C16 distance of 2.368 Å is typical for Zr−C σ bond,10
and the Zr−N bond length (2.379 Å) is in the typical range of
pyridine N-coordination.11 The chelate ring is nearly planar
with a torsion angle of C16−C15−N1−Zr to be 3.4°. The
allenic moiety is nearly linear (C16−C17−C18 174.6°). The
1H NMR spectrum of 2a′ in C6D6 showed a singlet Cp
resonance at 5.94 ppm, and an ortho proton adjacent to
nitrogen in pyridine ring appeared at 9.01 ppm. The 13C NMR
spectrum showed peaks at 111.6 and 196.4 ppm assignable for
Cp and C moiety, respectively. However, the in situ NMR
of the same reaction in toluene revealed that the methoxide
complex 2a was formed as a major zirconium species (63%
NMR yield) within 3 h. In this case, the methoxide-halide
exchange reaction might be hampered due to the low solubility
of LiCl in toluene.
a
Isolated yields. The ratio of diastereomers is shown in parentheses.
Unless noted, all the reactions were carried out using 1.6 equiv of
Negishi reagent and 2.0 equiv of aldehyde in toluene. 1.25 equiv of
Negishi reagent was used. Allenylzirconium was prepared in THF,
and the reaction with aldehydes was carried out by changing the
b
c
solvent to toluene.
Scheme 3
Computational Studies. To rationalize the regioselectivity
associated with the pyridine group in this reaction, density
functional theory (DFT)12 studies have been performed with
GAUSSIAN09 program13 using the M0614 method. For Zr the
Lanl2DZ basis set with Effective Core Potential (ECP)15 was
used; for the rest atoms, the 6-311+G** basis set was used.
Harmonic vibration frequency calculations were carried out, the
results show that all the optimized transition states with one
imaginary frequency. The energy of the reactant complex is
used as the zero point.8 Substrates 5, 1a and p-NO2C6H4CHO
were used in the calculation models. In the transition states, the
cyclohexane tail of the allenic moiety may point “up” or
“down”. In most cases, the “up” type is more stable due to
smaller intramolecular steric repulsion.
Chacterization of the Allenylzirconium Intermediate.
To have a deep insight into the molecular structure of the
allenylzirconium intermediate, we isolated the zirconium
complex 2a′ from the reaction of 1a with Cp2ZrBu2 in THF.
The X-ray crystal structure of 2a′ is shown in Figure 1. To our
surprise, the ORTEP plot shows that it is an allenylzirconium
chloride complex, but not an expected methoxide complex 2a.
The results indicated that a methoxide-halide exchange reaction
occurred during the process, which was induced by in situ
formed LiCl salt (Scheme 4). The two Cp rings and zirconium
atom exhibit a bent structure, and the angles between the
First, the reaction of the phenyl-substituted propargyl ether 5
was studied to be compared with. As shown in Figure 2, the
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Figure 2. Optimized α- and γ-addition transition states of 5 with p-NO2C6H4CHO. The selected bond lengths are in angstroms, and the relative free
energies ΔG(298K) are in kcal/mol.
most favorable γ-addition transition state Ph-TS-γ-up is 2.8
kcal/mol lower in energy than the best α-addition transition
state Ph-TS-α-up, indicating that the homopropargyl alcohol 6
is the dominant product. This result is consistent well with the
experimental observations (Scheme 3). In Ph-TS-α-up, one of
the ortho-hydrogen atoms of the phenyl group on the allenic
moiety is close to the hydrogen atoms of the aldehyde (2.083
Å) and the Cp ring (2.252 Å, 2.228 Å). These distances are
smaller than twice of the Van de Waals radius of hydrogen
(2.400 Å),16 showing that there are steric repulsions among the
phenyl group, the Cp ring and the aldehyde. However, in the
favorable transition state Ph-TS-γ-up the shortest H−H
distance between the phenyl group on the allenic moiety and
the Cp ring is 2.570 Å, larger than 2.400 Å, indicating there is
no repulsion between them. Ph-TS-α-down and Ph-TS-γ-
down are higher in energy. In these two structures, the collision
of the cyclohexane tail of the allenic moiety with the phenly
group of the aldehyde causes steric repulsion and entropy loss,
which should account for their instabilities.
Likewise, for the pyridyl-substituted propargyl ether 1a, four
transition states were located (Figure 3). The most favorable γ-
addition transition state Py-TS-γ-up is 0.6 kcal/mol higher than
the best α-addition transition state Py-TS-α-down, indicating
that the selectivity is reversed, the α-hydroxyallene 4 becomes
the important product. This result is qualitatively consistent
with the experimental observations (Table 2). Compared with
the α-addition transition states Ph-TS-α-down/up, in Py-TS-
α-down/up, one “C−H” moiety in the phenyl group is
changed to “N” atom in the pyridyl group, the “steric ortho-
hydrogen atom” does not exist any longer, releasing the steric
energy to some extent. Furthermore, amazingly, the N atom of
the pyridine ring can form hydrogen bondings17 with the
hydrogen atoms of the aldehyde (2.350, 2.621 Å in Py-TS-α-
down) and the Cp ring (2.605 Å in Py-TS-α-down). Thus, the
“steric repulsion” in Ph-TS-α-down/up becomes “stabilized
attraction” in Py-TS-α-down/up, switching the regioselectivity.
To confirm that the pyridyl group in the transition state does
not coordinate with the Zr center, the pyridyl-coordinated
models Py-TS-γ-up-N and Py-TS-γ-down-N were also
calculated. As shown in Figure 4, the coordination of the
pyridine group will cause so large steric repulsion at the
−
congested Zr center that the OMe anion is driven out of the
coordination sphere. Compared with Py-TS-γ-up, the relative
energy of Py-TS-γ-up-N increases dramatically by 28 kcal/mol.
The transition states Py-TS-α-up-N and Py-TS-α-down-N
were failed to be located possibly due to even larger steric
repulsion. Therefore, the reverse of the regioselectivity
originates from the following features of the pyridine ring:
(a) has smaller steric effect compared with the phenyl ring; (b)
the ability to form hydrogen bondings with hydrogen atoms of
the Cp ligand and the substrate.
In summary, we have demonstrated that the nucleophilic
addition reactions of pyridyl-substituted allenylzirconium
species to aldehydes proceeds regioselectively at the α-position
of the allenic moiety, leading to highly substituted α-
hydroxyallenes. The regioselectivity is quite different to that
of the reactions with allenyl/propargyl zirconium derived from
propargylic ethers without a pyridyl group reported so far. DFT
calculations suggest that the smaller steric effect of the pyridine
ring and its capability to form hydrogen bondings with
hydrogen atoms of the Cp ligand and the aldehyde may
account for the observed regioselectivity.
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Figure 3. Optimized α and γ-addition transition states of 1a with p-NO2C6H4CHO. The selected bond lengths are in angstroms, and the relative free
energies ΔG(298K) are in kcal/mol.
solution in hexane) at −78 °C. After stirring for 1 h at the same
temperature, γ-(2-pyridyl)propargyl methyl ether 1 (0.5 mmol) was
added and the reaction mixture was warmed up to room temperature
and stirred for 3 h. Aldehyde (1 mmol) was added and the reaction
mixture was stirred for 2 h. The resulting mixture was quenched with
saturated NaHCO3 solution and extracted with EtOAc. The extract
was washed with water, brine, and dried over anhydrous Na2SO4. The
solvent was evaporated under the reduced pressure and the residue
was purified by column chromatography on silica gel to afford the
desired products.
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of Allenes by the
Reaction of Cp2ZrBu2 with Propargyl Ethers. To a solution of
Cp2ZrCl2 (234 mg, 0.8 mmol) in THF (5 mL) was added dropwise of
n-BuLi (1.6 mmol, 1 mL, 1.6 M solution in hexane) at −78 °C. After
stirring for 1 h at the same temperature, γ-(2-pyridyl)propargyl methyl
ether 1 (0.5 mmol) was added and the reaction mixture was warmed
up to room temperature and stirred for 3 h. The reaction was
quenched with saturated NaHCO3 solution and extracted with EtOAc.
The extract was washed with water, brine, and dried over anhydrous
Na2SO4. The solvent was evaporated under the reduced pressure and
the residue was purified by column chromatography on silica gel to
afford the desired products.
1-(4-Chlorophenyl)-3-cyclohexylidene-2-(pyridin-2-yl)prop-
2-en-1-ol (4a). Column chromatography on silica gel (petroleum
ether/ethyl acetate = 15:1−10/1) afforded the title product as a yellow
1
solid in 56% yield. Mp 119−120 °C. H NMR (300 MHz, CDCl3) δ
2-(2-Cyclohexylidenevinyl)pyridine (3a). When THF was used
as a reaction solvent, 3a was obtained as a yellow oil in 83% yield by
column chromatography on silica gel (petroleum ether/ethyl acetate =
10/1). When toluene was used as a reaction solvent, 3a was obtained
1.18−1.60 (m, 6H), 2.02−2.09 (m, 4H), 5.82 (s, 1H), 6.58 (br, 1H),
7.05−7.09 (m, 1H), 7.28 (d, J = 8.7 Hz, 2H), 7.37−7.42 (m, 3H),
7.56−7.62 (m, 1H), 8.43 (d, J = 5.1 Hz, 1H). 13C NMR (75.5 MHz,
CDCl3) δ 25.63, 26.97, 27.08, 30.45, 30.58, 74.04, 106.90, 108.08,
121.05, 122.55, 127.78, 127.98, 132.34, 136.52, 141.64, 147.64, 156.89,
200.02. LRMS (EI) m/z 325 (M+). Anal. Calcd for C20H20ClNO: C,
73.72; H, 6.19; N, 4.30. Found: C, 73.72; H, 6.22; N, 4.25. IR (neat)
3373, 3053, 2853, 1953, 1591, 1562, 1471, 1433, 1343, 1089, 1014,
802, 785, 743 cm−1.
1
in 78% yield. H NMR (400 MHz, CDCl3) δ 1.55−1.71 (m, 6H),
2.21−2.31 (m, 4H), 6.19−6.28 (m, 1H), 7.00−7.04 (m, 1H), 7.38 (d, J
= 8.0 Hz, 1H), 7.56 (td, J = 7.8, 1.6 Hz, 1H), 8.49 (d, J = 4.4 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 25.82, 27.31, 30.82, 94.09, 106.74,
120.65, 120.75, 135.89, 149.11, 156.04, 201.54. HRMS (EI) calcd for
C13H15N 185.1204, found 185.1207. IR (neat) 2926, 2852, 1953,
1587, 1563, 1474, 1431, 831, 764, 740 cm−1.
General Procedure for the Synthesis of α-Hydroxyallenes
4a−4j. To a suspension of Cp2ZrCl2 (234 mg, 0.8 mmol) in toluene
(5 mL) was added dropwise of n-BuLi (1.6 mmol, 1 mL, 1.6 M
A Typical Procedure for the Synthesis of α-Hydroxyallenes
4k−4l. To a suspension of Cp2ZrCl2 (183 mg, 0.625 mmol) in THF
(5 mL) was added dropwise of n-BuLi (1.25 mmol, 0.78 mL, 1.6 M
solution in hexane) at −78 °C. After stirring for 1 h at the same
temperature, γ-(2-pyridyl)propargyl methyl ether 1 (0.5 mmol) was
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131.76, 132.07, 137.13, 137.14, 147.02, 148.03, 148.05, 149.95, 150.00,
154.46, 207.57, 207.87. HRMS (EI) calcd for C21H16N2O3 344.1161,
found 344.1158. IR (neat) 3368, 2926, 2855, 1938, 1591, 1519, 1471,
1345, 1046, 747, 695 cm−1.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, NMR spectra of all new products, CIF
files giving crystallographic data of compounds 2a′ and 4a, the
calculated reaction pathways, total energies and geometrical
coordinates. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Fax: (+86) 021-64166128. E-mail: yhliu@mail.sioc.ac.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Grant Nos. 21125210, 21072208, 21121062, 21172248),
Chinese Academy of Science and the Major State Basic
Research Development Program (Grant No. 2011CB808700)
for financial support.
REFERENCES
(1) Marshall, J. A. J. Org. Chem. 2007, 72, 8153.
(2) For regioselective reactions involving allenyl/propargyl metal
■
Figure 4. Optimized pyridine coordinated γ-addition transition states
of 1a with p-NO2C6H4CHO. The selected bond lengths are in
angstroms, and the relative free energies ΔG(298K) are in kcal/mol.
species, see: For Sn: (a) Kjellgren, J.; Sunden
Chem. Soc. 2004, 126, 474. For Ti: (b) Schultz-Fademrecht, C.;
́ ́
, H.; Szabo, K. J. Am.
Wibbeling, B.; Frohlich, R.; Hoppe, D. Org. Lett. 2001, 3, 1221. For
̈
Zn: (c) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Org. Chem. 1989,
54, 5198. (d) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1999, 64,
5201. (e) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1998, 63, 3812.
(f) Ma, S.; Zhang, A. J. Org. Chem. 1998, 63, 9601. (g) Ma, S.; Zhang,
A.; Yu, Y.; Xia, W. J. Org. Chem. 2000, 65, 2287. (h) Ma, S.; Wang, G.
Angew. Chem., Int. Ed. 2003, 42, 4215. For In: (i) Marshall, J. A.;
Grant, C. M. J. Org. Chem. 1999, 64, 696. (j) Marshall, J. A.; Grant, C.
M. J. Org. Chem. 1999, 64, 8214. For Sm: (k) Tabuchi, T.; Inanaga, J.;
Yamaguchi, M. Chem. Lett. 1987, 2275. (l) Mikami, K.; Yoshida, A.;
Matsumoto, S.; Feng, F.; Matsumoto, Y.; Sugino, A.; Hanamoto, T.;
Inanaga, J. Tetrahedron Lett. 1995, 36, 907. (m) Makioka, Y.; Koyama,
K.; Nishiyama, T.; Takaki, K. Tetrahedron Lett. 1995, 36, 6283. For
Ba: (n) Yanagisawa, A.; Suzuki, T.; Koide, T.; Okitsu, S.; Arai, T.
Chem. Asian J. 2008, 3, 1793. and references cited therein. For Li:
(o) Tokeshi, B. K.; Tius, M. A. Synthesis 2004, 786. (p) Brandsma, L.;
Nedolya, N. A. Synthesis 2004, 735. For B: (q) Canales, E.; Gonzalez,
A. Z.; Soderquist, J. A. Angew. Chem., Int. Ed. 2007, 46, 397.
(r) Fandrick, D. R.; Saha, J.; Fandrick, K. R.; Sanyal, S.; Ogikubo, J.;
Lee, H.; Roschangar, F.; Song, J. J.; Senanayake, C. H. Org. Lett. 2011,
13, 5616. For asymmetric allenylation of aldehydes with propargyl
bromides catalyzed by tethered bis(8-quinolinolato)(TBOx) chromi-
um complex, see: (s) Xia, G.; Yamamoto, H. J. Am. Chem. Soc. 2007,
129, 496. For reviews see: (t) Transition Metal Reagents and Catalysts:
Innovations in Organic Synthesis; Tsuji, J., Ed.; Wiley: Chichester, 2002;
Chapter 6. (u) Yamamoto, H. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2,
pp 81−98. (v) Marshall, J. A. Chem. Rev. 2000, 100, 3163. (u) Ma, S.
Eur. J. Org. Chem. 2004, 1175.
added and the reaction mixture was warmed up to room temperature
and stirred for 3 h. The solvent was removed in vacuo, and then
toluene (5 mL) was added. Aldehyde (1 mmol) was added and the
reaction mixture was stirred for another 2 h. The resulting mixture was
quenched with saturated NaHCO3 solution and extracted with EtOAc.
The extract was washed with water, brine, and dried over anhydrous
Na2SO4. The solvent was evaporated under the reduced pressure and
the residue was purified by column chromatography on silica gel to
afford the desired products.
4-(1-Hydroxy-2-(pyridin-2-yl)hepta-2,3-dien-1-yl)-
benzonitrile (4k). Column chromatography on silica gel (petroleum
ether/ethyl acetate =10/1, then petroleum ether/Et3N = 10/1)
afforded the title product as a yellow solid in 52% yield. The ratio of
1
the two diastereomers is 1.1:1. H NMR (400 MHz, CDCl3) two
isomers: δ 0.87 (t, J = 7.2 Hz), 1.33−1.38 (m), 1.97−2.03 (m), 5.52 (t,
J = 7.2 Hz), 5.85 (s), 5.88 (s), 7.09−7.12 (m), 7.46 (d, J = 12.0 Hz),
7.59−7.65 (m), 8.43 (d, J = 5.2 Hz). The chemical shift of OH proton
was not observed. 13C NMR (100 MHz, CDCl3) two isomers: δ 13.50,
13.51, 22.12, 22.16, 30.22, 30.31, 73.89, 74.08, 96.84, 96.86, 107.84,
107.92, 110.44, 110.46, 118.96, 121.44, 122.53, 122.55, 127.14, 127.20,
131.50, 136.71, 136.73, 147.66, 147.68, 148.26, 148.38, 155.62, 155.65,
205.00, 205.26. HRMS (EI) calcd for C19H18N2O 290.1419, found
290.1424. IR (neat) 3587, 2958, 2928, 2856, 2227, 1616, 1295, 1090,
742 cm−1.
1-(4-Nitrophenyl)-4-phenyl-2-(pyridin-2-yl)buta-2,3-dien-1-
ol (4l). 1.6 equiv Negishi reagent was used. Column chromatography
on silica gel (petroleum ether/ethyl acetate = 10/1) afforded the
product as a yellow solid in 41% yield. The ratio of the two
1
(3) For Zr: (a) Ito, H.; Nakamura, T.; Taguchi, T.; Hanzawa, Y.
Tetrahedron Lett. 1992, 33, 3769. (b) Ito, H.; Nakamura, T.; Taguchi,
T.; Hanzawa, Y. Tetrahedron 1995, 51, 4507. For Ti: (c) Okamoto, S.;
An, D. K.; Sato, F. Tetrahedron Lett. 1998, 39, 4551. (d) Yatsumonji,
Y.; Sugita, T.; Tsubouchi, A.; Takeda, T. Org. Lett. 2010, 12, 1968.
(e) Yang, F.; Zhao, G.; Ding, Y. Tetrahedron Lett. 2001, 42, 2839.
diastereomers is 2.3:1. H NMR (400 MHz, CDCl3) two isomers: δ
6.02 (s), 6.07 (s), 6.54−6.57 (m, 1H), 6.85 (s, 1H), 7.14−7.18 (m,
1H), 7.23−7.33 (m, 5H), 7.48−7.49 (m, 1H), 7.60−7.69 (m, 3H),
8.08−8.13 (m, 2H), 8.49−8.51 (m, 1H). 13C NMR (100 MHz,
CDCl3) two isomers: δ 73.75, 74.51, 100.15, 111.66, 122.25, 123.07,
123.12, 126.93, 126.97, 127.15, 127.30, 127.99, 128.02, 128.85, 128.89,
1641
dx.doi.org/10.1021/om301007z | Organometallics 2013, 32, 1636−1642

Organometallics
Article
(f) Nakagawa, T.; Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 36,
3207. (g) Kasatkin, A.; Sato, F. Angew. Chem., Int. Ed. 1996, 35, 2848.
(4) For the generation of allenyl/propargyl titanium species via
transmetalation, see: (a) Furuta, K.; Ishiguro, M.; Haruta, R.; Ikeda,
N.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1984, 57, 2768. (b) Schultz-
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,
Revision A.02; Gaussian, Inc.: Wallingford CT, 2009.
(14) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215−241.
(15) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299−310.
(16) Bondi, A. J . Phys. Chem. 1964, 68, 441.
(17) (a) Taylor, R.; Kennard, O. J. Am. Chem. Soc. 1982, 104, 5063−
5070. (b) Corey, E. J.; Lee, T. W. Chem. Commun. 2001, 1321.
Fademrecht, C.; Wibbeling, B.; Frohlich, R.; Hoppe, D. Org. Lett.
̈
2001, 3, 1221. (c) Zimmermann, M.; Wibbeling, B.; Hoppe, D.
Synthesis 2004, 765.
(5) For allenylzirconocene complexes prepared by other methods,
see: (a) Suzuki, N.; Hashizume, D. Coord. Chem. Rev. 2010, 254, 1307.
(b) Xi, C.; Yan, X.; You, W.; Takahashi, T. Angew. Chem., Int. Ed.
2009, 48, 8120. (c) Ugolotti, J.; Kehr, G.; Frohlich, R.; Grimme, S.;
̈
Erker, G. Chem. Commun. 2009, 6572. (d) Ugolotti, J.; Kehr, G.;
Frohlich, R.; Grimme, S.; Erker, G. J. Am. Chem. Soc. 2009, 131, 1996.
̈
(e) Ugolotti, J.; Dierker, G.; Kehr, G.; Frohlich, R.; Grimme, S.; Erker,
̈
G. Angew. Chem., Int. Ed. 2008, 47, 2622. (f) Binger, P.; Langhauser,
F.; Gabor, B.; Mynott, R.; Herrmann, A. T.; Kruger, C. J. Chem. Soc.,
̈
Chem. Commun. 1992, 505. (g) Pellny, P.-M.; Kirchbauer, F. G.;
Burlakov, V. V.; Baumann, W.; Spannenberg, A.; Rosenthal, U.
Chem.Eur. J. 2000, 6, 81. (h) Suzuki, N.; Hashizume, D.; Koshino,
H.; Chihara, T. Angew. Chem., Int. Ed. 2008, 47, 5198. (i) Zhang, S.;
Zhang, W.; Zhao, J.; Xi, Z. J. Am. Chem. Soc. 2010, 132, 14042.
(6) Zhang, H.; Fu, X.; Chen, J.; Wang, E.; Liu, Y.; Li, Y. J. Org. Chem.
2009, 74, 9351.
(7) For regioselective addition of allylmetal species containing a
heteroatom substituent with aldehydes, see: (a) Hoppe, D.;
Lichtenberg, F. Angew. Chem., Int. Ed. 1982, 21, 372. (b) Weidmann,
B.; Seebach, D. Angew. Chem., Int. Ed. 1983, 22, 31. (c) Zubaidha, P.
K.; Kasatkin, A.; Sato, F. J. Chem. Soc. Chem. Commun. 1996, 197.
(8) See Supporting Information.
(9) For reviews, see: (a) Takahashi, T.; Kanno, K. Top. Organomet.
Chem. 2005, 8, 217. (b) Liu, R.; Zhou, X. J. Organomet. Chem. 2007,
692, 4424. (c) Xi, Z.; Kong, F.; Zheng, W.-X.; Zhang, W.-X. Chin. J.
Org. Chem. 2005, 25, 229. For recent reports, see: (d) Takahashi, T.;
Kuzuba, Y.; Kong, F.; Nakajima, K.; Xi, Z. J. Am. Chem. Soc. 2005, 127,
17188. (e) Xi, Z.; Sato, K.; Gao, Y.; Lu, J.; Takahashi, T. J. Am. Chem.
Soc. 2003, 125, 9568. (f) Takahashi, T.; Song, Z.; Hsieh, Y.; Nakajima,
K.; Kanno, K. J. Am. Chem. Soc. 2008, 130, 15236. (g) Dzwinniel, T.
L.; Stryker, J. M. J. Am. Chem. Soc. 2004, 126, 9184. (h) Dzwinniel, T.
L.; Etkin, N.; Stryker, J. M. J. Am. Chem. Soc. 1999, 121, 10640.
(i) Crowe, W. E.; Vu, A. T. J. Am. Chem. Soc. 1996, 118, 5508.
(j) Gleiter, R.; Wittwer, W. Chem. Ber. 1994, 127, 1797. (k) Giolando,
D. M.; Rauchfuss, T. B. J. Am. Chem. Soc. 1984, 106, 6455.
(l) Takahashi, T.; Song, Z.; Kuzuba, Y.; Sato, K.; Nakajima, K.;
Kanno, K. J. Am. Chem. Soc. 2007, 129, 11678. (m) Ren, S.; Igarashi,
E.; Nakajima, K.; Kanno, K.; Takahashi, T. J. Am. Chem. Soc. 2009,
131, 7492.
(10) (a) Thomas, D.; Baumann, W.; Spannenberg, A.; Kempe, R.;
Rosenthal, U. Organometallics 1998, 17, 2096. (b) Spannenberg, A.;
Arndt, P.; Baumann, W.; Burlakov, V.; Rosenthal, U.; Becke, S.; Weiss,
T. Organometallics 2004, 23, 3819.
(11) Kempe, R.; Brenner, S.; Arndt, P. Organometallics 1996, 15,
1071.
(12) (a) Hohenberg, P.; Kohn, W. Phys. Rev. 1964, 136, B864.
(b) Kohn, W.; Sham, L. J. Phys. Rev. 1965, 140, A1133.
(13) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G..; Barone, V.; Mennucci,
B.; Petersson, G.. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G..; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;. Montgomery, A. Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;
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