Low-valent titanium induced novel reductive cyclizations of α,β- unsaturated nitrile compounds

Article abstract of DOI:10.1055/s-1998-2082

The intermolecular and intermolecular reductive coupling reactions of α,β-unsaturated nitrile derivatives induced by a low-valent titanium reagent prepared from titanium tetrachloride and zinc powder were studied. The configuration of cyclodimerization pr

Full text of DOI:10.1055/s-1998-2082

June 1998
SYNTHESIS
851
a b
Low-Valent Titanium Induced Novel Reductive Cyclizations of , -Unsaturated Nitrile
Compounds
Long-hu Zhou,*a Shu-jiang Tu,a Da-qin Shi,a Gui-yuan Dai,a Wei-xing Chenb
a Department of Chemistry, Xuzhou Normal University, Xuzhou, 221009, People’s Republic of China
b Department of Chemistry, Nanjing University, Nanjing, 210008, People’s Republic of China
Received 26 September 1997; revised 17 November I997
Abstract: The intermolecular and intramolecular reductive cou-
pling reactions of a,b-unsaturated nitrile derivatives induced by a
low-valent titanium reagent prepared from titanium tetrachloride
and zinc powder were studied. The configuration of cyclodimer-
ization product was confirmed by X-ray analysis.
Key words: cyclopentenes, reductive cyclization, 2-aminoquino-
lines, low-valent titanium, a,b-unsaturated nitriles
2
Ar
R
2
Ar
R
Low-valent titanium reagents have an exceedingly high
ability in promoting the reductive coupling of carbonyl
compounds and are attracting increasing interest in organ-
ic synthesis. A lot of other functional groups can also be
coupled.1, 2 Although several results are reported on satu-
rated carbonyl compounds, only a few studies concerning
a,b-unsaturated carbonyl compounds have been pub-
lished. Recently, we reported the cyclodimerization of
a,b-unsaturated ketones promoted by this reagent to yield
cyclopentane derivatives.3 It has been known that a,b-un-
saturated carboxylic acid derivatives are reduced with
samarium diiodide to the corresponding saturated com-
pounds,4 but there is no report on such a reaction using
low-valent titanium. Here, we wish to report the novel re-
ductive cyclization of a,b-unsaturated nitrile derivatives
promoted by treatment with titanium tetrachloride/zinc in
anhydrous tetrahydrofuran.
a
b
c
d
e
4-ClC6H4
2-ClC6H4
4-MeC6H4
4-BrC6H4
Ph
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
f
3,4-OCH2OC6H3 CO2Et
3-OH,4-OMeC6H3 CO2Et
4-ClC6H4
Ph
g
h
i
CN
Ph
reaction conditions and have no influence on the rate of
cyclodimerization (1a–f). Substrate 1g which contains a
hydroxy group is not as reactive as the other substrates ex-
amined and requires longer reaction times. (p-Chloroben-
zylidene)malononitrile (1h) and a-phenylcinnamonitrile
(1i) can also give the corresponding cyclodimerization
products. However, 1h has higher reactivity, while 1i has
lower reactivity and needs longer reaction times. When
ethyl cinnamate was treated with the same reagent under
the same reaction conditions, the reductive cyclization
could not take place, even under refluxing conditions
overnight, and the substrate could be recovered. All cy-
clodimerization reactions are highly stereoselective as
only one isomer was obtained and the careful analysis of
the reaction mixture indicated the absence of the other ste-
reoisomer. This could be confirmed by the X-ray crystal
structure analysis of the product 2a, which clearly demon-
strate the trans-trans stereochemistry of the product (Fig-
ure). The atoms C(7), C(8), C(9), C(10), and C(11) form
a central 5-ring. The alkoxycarbonyl group at C(8) is in
the equatorial position. The phenyl groups at C(7) and
C(11) are in equatorial positions and form angles of 70.67
and 66.74° with the central 5-ring respectively. The two
phenyl groups form an angle of 92.68° with each other.
The delocalization between the donor N(1) and the accep-
tor alkoxy carbonyl group (1) is reflected in the molecular
dimensions: the C(9)–C(10) distance of 1.359(5)Å is sig-
nificantly longer than the C=C bond in ethylene
(1.336(2)Å.7 There is a corresponding shortening of the
C(9)–N(1) [1.350 (5)Å] bond relative to the normal
C(sp2)–N (1.426Å) bond.8
It has been known that the cyano group is relatively more
stable to low-valent titanium reagent than the carbonyl
group and could not be reduced unless the reaction mix-
ture was refluxed for a long time and only with low reac-
tion yield in our previous reports.5, 6 We considered that
the conjugated carbon–carbon double bond could perhaps
influence the reactivity of the cyano group. Therefore, we
have studied the behavior of the cyano group in a,b-un-
saturated nitrile derivatives when treated with titanium
tetrachloride and zinc in anhyd tetrahydrofuran.
As expected, the reactivity of the cyano group of the a,b-
unsaturated nitrile compounds is much higher than that of
the saturated nitriles. When a,b-unsaturated nitrile deriv-
atives 1 were treated with titanium tetrachloride and zinc
in tetrahydrofuran, the cyclodimerization products 2,
which are different from the products of the saturated ni-
trile compounds,5, 6 were obtained.
The reaction for various a,b-unsaturated nitrile com-
pounds promoted by low-valent titanium reagent was ex-
amined and our cyclization results are summarized in the
Table. In all the reactions, the cleavage takes place selec-
tively at the cyano group, rather than at the alkoxycarbo-
nyl group. At the same time, chloro, bromo, and alkoxy
groups in the aromatic ring could not be reduced under the
However, treatment of ethyl a-cyano-a-(p-nitroben-
zylidene)acetate (3) with titanium tetrachloride and zinc
in anhyd tetrahydrofuran under the same reaction condi-

852
Papers
SYNTHESIS
as internal standard, chemical shifts are reported in d units (ppm). MS
were recorded on a ZAB-HS spectrometer. Microanalyses were car-
ried out on a Perkin–Elmer 240C instrument. X-ray diffraction was
recorded on a Rigaku AFC7R diffractometer.
Cyclopentenes 2: General Procedure:
TiCl4 (2.2 mL, 20 mmol) was added dropwise using a syringe to a
stirred suspension of Zn powder (2.6 g, 40 mmol) in freshly distilled
anhyd THF (20 mL) at r.t. under N2. On completion of the addition,
the mixture was refluxed for 2 h. The black suspension of the low-va-
lent titanium reagent formed was allowed to cool to r.t. and a solution
of a,b-unsaturated nitrile (10 mmol) in THF (10 mL) was added drop-
wise over ca. 20 min. The mixture was stirred at r.t. under N2. When
the reaction was complete, most of the solvent was removed under re-
duced pressure. The residue was quenched with 3% HCl (50 mL) and
extracted with CHCl3 (3 ´ 50 mL). The combined organic layers were
washed with water (2 ´ 30 mL), dried (Na2SO4), and the solvent was
removed in vacuo to give the crude product, which was further puri-
fied by column chromatography [silica gel, EtOAc/petroleum ether
(bp 60–90°C),1:4] (Table).
Figure. X-ray Crystallographic Structure of 2a.13
Products 4 and 5:
A black suspension of low-valent titanium reagent was prepared with
TiCl4 (40 mmol) and Zn powder (80 mmol) in THF (40 mL) using the
same procedure mentioned above. A solution of ethyl a-cyano-a-(p-
nitrobenzylidene)acetate (3) (10 mmol) in THF (20 mL) was added
carefully to the suspension at r.t. The mixture was stirred for 1 h at r.t.
under N2, and most of the solvent was then removed in vacuo. The
residue was poured into 10% K2CO3 (200 mL), and extracted with
CHCl3 (4 ´ 50 mL). The combined extracts were washed with water
(2 ´ 30 mL), dried (Na2SO4), and the solvent was removed in vacuo
to give the crude product, which was further purified by column chro-
matography [silica gel, EtOAc/petroleum ether (bp 60–90°C),1:1]
(Table).
tions afforded cyclopentene 5 along with the correspond-
ing product 4 formed by reduction of the nitro group in 3.
On the other hand, when a-cyano-a-(o-nitroben-
zylidene)acetate or (o-nitrobenzylidene)malononitrile de-
rivatives 6 were subjected to the above procedure, no
products 4 or 5 were detected. However, the intramolecu-
lar reductive cyclization product, 2-aminoquinoline deriv-
atives 7, were found in good purity and high yields.
2-Aminoquinolines 7: General Procedure:
A solution of the appropriate substrate 6 (10 mmol) in anhyd THF
(20 mL) was added carefully at r.t. to a suspension of low-valent tita-
nium reagent (40 mmol) prepared as mentioned above. When the re-
action was complete (at r.t. under N2), most of the solvent was
removed in vacuo. The residue was poured into 10% K2CO3 (200
mL), and extracted with CHCl3 (4 ´ 50 mL). The combined organic
layers were washed with water (2 ´ 30 mL), dried (Na2SO4), and the
solvent was removed in vacuo to give the crude product. This was fur-
ther purified by recrystallization from the appropriate solvent (Table).
Crystal Structure Analysis of 2a:13
Crystal data: C24H22Cl2N2O4, colorless; approximate dimensions:
0.20 ´ 0.20 ´ 0.30 mm3, Mr = 473.35 gmol–1, monoclinic, space group
P21/c (#14), a = 6.923(1), b = 33.178(5), c = 10.644(3)Å, b = 99.86(2)°,
V = 2408.8(8)Å3, Z = 4, Dc = 1.305 g·cm–3 M0-Ka radiation, l =
0.71069Å (graphite monochromator), m(M0Ka) = 3.01 cm–1.
Data Collection: The intensity data for the compound were collected on
a Rigaku AFC7R diffractometer, using the w-2q technique at 20°C.
3367 reflections were measured, of which 3308 were independent re-
flections with 2q in the range of 6 ~49.8°, 2147 reflections having I>3s
(I). The data were corrected for Lorentz and polarization effects.
Structure Solution and Refinement: The structure was solved by direct
methods (SHELXS-86)10 and expanding using Fourier techniques
(DIRDIF-92).11 The non-hydrogen atoms were refined anisotropical-
ly. Hydrogen atoms were included but not refined. The final cycle of
full-matrix least-squares refinement converged with unweighted and
weighted agreement factors of R = 0.052 and Rw = 0.067. The maxi-
mum and the minimum peak on the final difference Fourier map cor-
responded to 0.28 and –0.26 e/Å3, respectively. All calculations were
performed using TEXSAN program package.12
6, 7
R
R¢
a
b
c
H
H
CO2Et
CN
CO2Et
CN
4,5-OCH2OC6H3
4,5-OCH2OC6H3
d
In summary, we have found a novel cyclodimerization of
a,b-unsaturated nitrile compounds promoted by low-va-
lent titanium reagent and a facile synthesis of 2-amino-
quinoline derivatives with this reagent.
THF was distilled from LiAlH4 prior to use. All mps are uncorrected.
IR spectra were recorded in KBr disks using a FTIR-8101 spectro-
photometer. The 1H NMR spectra were recorded on a JOEL JNMFX-
90Q or Bruker AZ-300 spectrometer with CDCl3 as solvent and TMS

June 1998
SYNTHESIS
853

854
Papers
SYNTHESIS
Financial support of this research from the Education Committee
Nature Science Foundation of Jiangsu Province is gratefully
acknowledged.
(11) Beurskens, P. T.; Admiral, G.; Beurskens, G.; Bosman, W. P.;
Garcia-Granda, S.; Gould, R. O.; Smits, J. M. M.; Smykalla, C.
DIRDIF-92, The DIRDIF Program System, Technical Report of
the Crystallography Laboratory, University of Nijmegen, The
Netherlands, 1992.
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tural Corporation, 1985 & 1992.
(3) Zhou, L. H.; Shi, D. Q.; Gao, Y.; Shen, W. B.; Dai, G. Y.; Chen,
W. X. Tetrahedron Lett. 1997, 38, 2729.
(4) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980,
102, 2693.
(5) Chen, W. X.; Zhang, J. H.; Hu, M. Y.; Wang, X. C. Synthesis
1990, 701.
(6) Chen, J. X.; Jiang, J. P.; Chen, W. X.; Kao, T. Y. Heterocycles
1991, 32, 2339.
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Young, J. E. J. Chem. Phys. 1965, 42, 2683.
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Acta Crystallogr. Sect. C: Cryst. Struct. Commun. 1989, C45,
1722.
(13) Selected bond lengths(Å): Nl–C91.350(5); C9–C10 1.359(5);
Cl0–C22 1.445(5); C10–C11 1.520(5); C11–C13 1.516(5);
C7–C11 1.551(5); C6–C7 1.511(5); C7–C81.580(5); C8–C9
1.524(5); C8–C12 1.479(6); C8–C19 1.526(6). Selected bond
angles (°): C6–C7–C8 114.1(3); C6–C7–C11 117.1(3);
C8–C7–C11 104.2(3); C7–C8–C9 102.2(3); C7–C8–Cl2
112.3(3); C7–C8–C19 109.9(3); C9–C8–C12 108.1(3);
C9–C8–C19 115.8(3); Cl2–C8–C19 108.6(3); N1–C9–C8
120.0(3); N1–C9–C10 129.4(4); C8–C9–C10 110.2(3);
C9–C 10–C11 112.6(3); C9–C10–C22 122.4; C11–C 10–C22
124.7(3); C7–C11–C10 102.3(3); C7–C 11–C13 121.1(3);
C10–C11–C13 114.1(3). Supplementary material: Atomic
coordinates, bond lengths and angles, torsion angles and ther-
mal parameters have been deposited at the Crystallographic
Center of Shanghai Institute of Organic Chemistry.
(9) Tyler, J. M. J. Chem. Soc. 1955, 203.
(10) Sheldrick, G. M. SHELXS-86, In Crystallographic Computing
3; Sheldrick, G. M., Kruger, C.; Goddard, R. Eds.; Oxford Uni-
versity Press: Oxford, 1986; p 175.