Photoinduced tandem three-component coupling of propanedinitrile, 2,5-dimethylhexa-2,4-diene, and cyanoarenes

Article abstract of DOI:10.1021/jo801624q

(Chemical Equation Presented) A tandem three-component coupling photoreaction proceeds upon photoirradiation of MeCN/H₂O solutions containing propanedinitrile (1, malononitrile), 2,5-dimethylhexa-2,4-diene (2), and polycyanoarenes in the presence of phenanthrene and carbonate, leading to selective α-monoalkylation of 1. The reaction proceeds via photo-NOCAS (Nucleophile-Olefin Combination, Aromatic Substitution) type mechanism: nucleophilic attack of the anion of 1 to photogenerated 2^?+ is followed by ipso-substitution on the radical anion of the polycyanoarene. It advances under mild, safe, and environmentally friendly conditions such as proceeding at ambient temperature without metals and halogens, and in the presence of weak base. The reaction also represents a novel and metal-free cross-coupling reaction that leads to ipso-substitution on polycyanoarene via aryl-cyano bond cleavage. In addition, the reaction is a rare example of introducing carbon nucleophile in the photoinduced electron transfer reaction, except that of cyanide ion.

Full text of DOI:10.1021/jo801624q

Photoinduced Tandem Three-Component Coupling of
Propanedinitrile, 2,5-Dimethylhexa-2,4-diene, and Cyanoarenes
Maki Ohashi, Keisuke Nakatani, Hajime Maeda, and Kazuhiko Mizuno*
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture UniVersity, 1-1
Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan
mizuno@chem.osakafu-u.ac.jp
ReceiVed July 23, 2008
A tandem three-component coupling photoreaction proceeds upon photoirradiation of MeCN/H2O solutions
containing propanedinitrile (1, malononitrile), 2,5-dimethylhexa-2,4-diene (2), and polycyanoarenes in
the presence of phenanthrene and carbonate, leading to selective R-monoalkylation of 1. The reaction
proceeds via photo-NOCAS (Nucleophile-Olefin Combination, Aromatic Substitution) type mechanism:
nucleophilic attack of the anion of 1 to photogenerated 2•+ is followed by ipso-substitution on the radical
anion of the polycyanoarene. It advances under mild, safe, and environmentally friendly conditions such
as proceeding at ambient temperature without metals and halogens, and in the presence of weak base.
The reaction also represents a novel and metal-free cross-coupling reaction that leads to ipso-substitution
on polycyanoarene via aryl–cyano bond cleavage. In addition, the reaction is a rare example of introducing
carbon nucleophile in the photoinduced electron transfer reaction, except that of cyanide ion.
Introduction
metrically disubstituted products,2 and due to oligomerization
of the anion intermediates.1
To circumvent this difficulty, we have chosen a photochemi-
cal method5 instead of using strong bases, and just reported a
novel method for R-monoalkylation of 1, which proceeds
selectively under mild conditions (eq 1).6
The linkage chains to tether two building blocks into
intramolecular dyads are important for the development of
highly functionalized molecules. One of the most commonly
used tools for this purpose is sequential SN2 reactions of the
anion of propanedinitrile (1, malononitrile)1-3 along with those
of other active methylene compounds,4 arising from their
reactivity and commercial availability. However, these reactions
often resulted in low yield due to overreaction to give sym-
* Address correspondence to this author. Phone: +81-72-254-9289. Fax: +81-
72-254-9289.
(1) For reviews, see: (a) Freeman, F. Chem. ReV. 1969, 69, 591–624. (b)
Fatiadi, A. J. Synthesis 1978, 165–204. (c) Fatiadi, A. J. Synthesis 1978, 241–
282.
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1989, 391–393, and the references cited herein.
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Mukae, H.; Maeda, H.; Mizuno, K. Angew. Chem., Int. Ed. 2006, 45, 6558–
6560. Mukae, H.; Maeda, H.; Mizuno, K. Angew. Chem. 2006, 118, 6708–6710.
(4) (a) Adams, R.; Kamm, R. M. Org. Synth. 1925, 4, 11–12. (b) Krapcho,
A. P. Synthesis 1982, 805–822. (c) Krapcho, A. P. Synthesis 1982, 893–914. (d)
Cope, A. C.; Holmes, H. L.; House, H. O. Org. React. 1957, 9, 107–331. (e)
McMurry, J. E.; Musser, J. H. J. Org. Chem. 1975, 40, 2556–2557. (f) Tiete,
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Conway, W. P.; Strege, P. F.; Dietsche, T. J. J. Am. Chem. Soc. 1974, 96, 7165–
7167.
In this work, we expanded this strategy to develop a three-
component coupling reaction, the so-called photo-NOCAS
(Nucleophile-Olefin Combination, Aromatic Substitution) reac-
tion,7 to obtain tandem R-monoalkylation product of 1 in high
yield.
(5) Neunteufel, R. A.; Arnold, D. R. J. Am. Chem. Soc. 1973, 95, 4080–
4081.
(6) Ohashi, M.; Nakatani, K.; Maeda, H.; Mizuno, K. Org. Lett. 2008, 10,
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cited therein.
8348 J. Org. Chem. 2008, 73, 8348–8351
10.1021/jo801624q CCC: $40.75 2008 American Chemical Society
Published on Web 10/11/2008

Photoinduced Tandem Three-Component Coupling
TABLE 1. Coupling Reaction of Dicyanobenzenesa
introducing a carbon nucleophile into a photoinduced electron
transfer (PET) reaction, except that of a cyanide ion.6,11
Not a monosubstituted product 7 but a 1,3-disubstituted one
8 is obtained in 64% yield when 1,2,4,5-tetracyanobenzene (6)
is employed instead of 3 in the photoreaction (eq 3). This means
that 6 undergoes the three-component coupling twice: that is,
the first coupling among 1, 2, and 6 leads to the primary product
7, which is rapidly consumed by the second regioselective
coupling reaction with 1 and 2 to form 8. The primary
photoproduct 7 can be obtained (58%) along with 8 (11%) and
5 (22%) in the absence of Phen. This result and that of o-3
described above indicate that Phen acts as a reaction accelerator
by mediating the electron transfer (acting as a redox photosen-
sitizer or a cosensitizer)8 to suppress the back electron transfer
(BET) deactivation process.
yieldsb/%
entry
dicyanobenzene
4
5
1
2
3
p-3
o-3
m-3
87
52
0
25
37
47
a Conditions: 300-W high-pressure mercury lamp, Pyrex filter, 1 (2.5
mmol), 2 (75 µmol), 3 (25 µmol), Phen (25 µmol), Na2CO3 (1.25
mmol), MeCN (4 mL), H2O (1 mL), under Ar, rt, 20 h. b Determined by
1H NMR based on the amount of 3 (for 4) and 2 (for 5) used.
Results and Discussion
Three-Component Coupling Reaction of Cyanobenzenes. Pho-
toirradiation of an aqueous acetonitrile solution containing
malononitrile (1), 2,5-dimethylhexa-2,4-diene (2), and p-dicy-
anobenzene (p-3) in the presence of phenanthrene (Phen)8 and
an excess amount of sodium carbonate gives a good yield of
three-component coupling product p-4 (87% based on the
amount of p-3 used) along with propanedinitrile-incorporated
dimer 5 (25% based on the amount of 2 used) (eq 2, and entry
1 of Table 1). The use of o-dicyanobenzene (o-3) also results
in the formation of corresponding photoproduct o-4 (52%)
together with dimer 5 (37%) (entry 2), while m-dicyanobenzene
(m-3) affords a better yield of 5 (47%) as the sole product (entry
3). These reactions also proceed in the absence of Phen, but
the yield of 4 decreases (38%) when initiated with o-3.
The structures of all the photoproducts were determined by
1
their spectral data of H and 13C NMR, MS, HRMS, and IR.
An X-ray crystallographic analysis was also performed for a
single crystal of 7 to confirm its structure (Supporting Informa-
tion, Figure S1). The disubstituted product 8 was determined
as 1,3-disubstituted regioisomer since two resonances appeared
in the aromatic region of its 1H NMR spectrum, while only one
identical proton is expected for each of the other possible
regioisomers (1,2- and 1,4-product).
Effects of Carbonates. Metal salts are known to play an
important role in the reactions containing ionic intermediates, by
promoting their charge separation.12 We have also reported the
effect on the various photoinduced electron transfer reactions to
drastically improve the efficiency and selectivity.13 In this course,
we checked the salt dependency of the photoreaction of p-3 (entries
1-3, Table 2) and 6 (entries 4-6) by changing the alkali
counterions of the carbonate and found that a use of heavier alkali
ion leads to a better yield of the coupling products p-4 and 8. This
result is presumably due to the charge separation effect of softer
This tandem three-component reaction not only broadens the
synthetic usability of the photochemical R-monoalkylation
method of 1 that we have reported,6 but also enables us to
accomplish photoinduced cross coupling under mild and safe
conditions such as ambient temperature and in the presence of
water and weak base, employing a cyano group as a leaving
group. While cleavage of the carbon-cyano bond has been
highlighted during recent years but is still a challenging task,7,9,10
this metal-free photoreaction offers a novel methodology of
activating aryl-cyano bonds. Besides, this is a rare example of
TABLE 2. Effects of Carbonatesa
entry
cyanobenzene
carbonate
products (yieldsb/%)
(8) Majima, T.; Pac, C.; Nakasone, A.; Sakurai, H. J. Am. Chem. Soc. 1981,
103, 4499–4508.
(9) For a review, see: Tobisu, M.; Chatani, N. Chem. Soc. ReV. 2008, 37,
300–307.
(10) (a) Tobisu, M.; Kita, Y.; Chatani, N. J. Am. Chem. Soc. 2006, 128,
8152–8153. (b) Nakao, Y.; Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2004, 126,
13904–13905. (c) Zhang, M.; Lu, Z.-F.; Liu, Y.; Grampp, G.; Hu, H.-W.; Xu,
J.-H. Tetrahedron 2006, 62, 5663–5674.
(11) (a) Mizuno, K.; Pac, C.; Sakurai, H. J. Chem. Soc., Chem. Commun.
1975, 553. (b) Maroulis, A. J.; Shigemitsu, Y.; Arnold, D. R. J. Am. Chem. Soc.
1978, 100, 535–541. (c) Yasuda, M.; Pac, C.; Sakurai, H. J. Chem. Soc., Perkin
Trans. 1 1981, 746–750. (d) Kitagawa, F.; Murase, M.; Kitamura, N. Chem.
Lett. 2001, 786–787. (e) Ohashi, M.; Maeda, H.; Mizuno, K. Chem. Lett. 2006,
35, 482–483.
1
2
3
4
5
6
p-3
p-3
p-3
6
6
6
Li2CO3
Na2CO3
K2CO3
Li2CO3
Na2CO3
K2CO3
p-4 (84)
p-4 (87)
p-4 (96)
8 (18)
8 (64)
8 (56)
5 (23)
5 (25)
5 (25)
5 (36)
5 (15)
5 (25)
a Conditions: 300-W high-pressure mercury lamp, Pyrex filter, 1 (2.5
mmol), 2 (75 µmol), p-3 or 6 (25 µmol), Phen (25 µmol), carbonate
(1.25 mmol), MeCN (4 mL), H2O (1 mL), under Ar, rt, 20 h.
b Determined by 1H NMR based on the amount of cyanobenzene (for
p-4 and 8) and 2 (for 5) used.
J. Org. Chem. Vol. 73, No. 21, 2008 8349

Ohashi et al.
SCHEME 1. A Plausible Mechanism for the Formation of 4 and 5 via Path I
SCHEME 2. A Plausible Mechanism for the Formation of
A• via Path II
(Inductively Coupled Plasma-Atomic Emission Spectrometry)
analysis was performed to determine the solubility of sodium
carbonate as 1.8 × 10-5 M. From this value and known pKa
values for the carbonate and 1,14 the concentration of the anion
of 1 was calculated to be around 2 × 10-5 M. Since this value
is about 800 times smaller than that of 2 (15 mM) and efficient
exergonic SET is predicted for both paths,15 we concluded that
path I is the major path, although these are in competition. In
fact, the PET reaction occurs even in the absence of 1, producing
dihydroxy-incorporated dimer 9 (eq 4); that is, 2•+ formed by
an electron transfer is captured by water (or formally hydroxide
ion) as a weak nucleophile, and the resulting radical undergoes
dimerization to give 9.
metal salts (via interaction between the photogenerated radical ion
pair and the salts) to suppress BET, which is consistent with the
acceleration effect of electron-mediating Phen (vide supra).
A Plausible Mechanism. We propose that the reaction is
promoted by single electron transfer (SET) from the excited singlet
state of Phen (1Phen*) to 3, followed by a secondary SET from 2
to Phen•+ (Scheme 1).8 SET from Phen or 2 to 13* (or 16* in the
case of eq 3) can also take place. These processes afford 2•+, which
is trapped by the anion of 1 to form an allylic radical intermediate
A• (path I). An alternative pathway might involve SET from the
anion of 1 to Phen•+, followed by coupling of the resulting radical
with 2 to form A• (path II, Scheme 2). Radical coupling between
A• and 3•- takes place to give B-. Stabilization of the anion charge
of B- by a cyano group on the ortho- or para-position of the former
benzene ring is crucial for the success of the radical coupling (entry
3, Table 1). Elimination of cyanide ion from the ipso-position of
B- regenerates the aromaticity of the benzene ring to afford three-
component coupling product 4.7 If A• diffuses out of the solvent
cage, it dimerizes regioselectively at its terminal position to produce
5, a result that correlates with the relative stabilities of the three
possible dimers. The third competitive pathway for the consumption
of A• is the BET from 3•-, but the resulting anion A- dissociates
spontaneously (∆Gq ≈ 2 kcal/mol by HF/3-21G) to form the
starting materials (i.e., the anions of 1 and 2).
The low concentration of the anion of 1 described above is
the feature of our photoreaction system. Nucleophilic species
usually have lower oxidation potential than that of alkenes.
Therefore, their coexistence at similar concentration in the
reaction mixture results in exclusive one-electron oxidation of
nucleophiles, not alkenes, and the resulting radicals tend to
dimerize or give complex product mixtures. One of the solutions
for this problem presented from electroorganic chemists is the
separation of active sites, or concentration effects,16 which uses,
for example, adsorption of alkenes on anodes, diffusion of the
alkene radical cations over a boundary of two liquid phases, or
solid-supported nucleophiles to localize the existence of nu-
cleophilic species. Our reaction system employs in situ genera-
To elucidate whether path I or II is dominant, the concentra-
tion of the anion of 1 was estimated as follows: An ICP-AES
(14) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.;
Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.; McCollum,
G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006–7014.
(15) ∆GSET )-0.29 (path I) and-0.92 eV (path II), according to the redox
potentials of the reactants; Cf.: Rehm, D.; Weller, A. Isr. J. Chem 1970, 8, 259–
271.
(12) For reviews, see: (a) Loupy, A.; Tchoubar, B.; Astruc, D. Chem. ReV.
1992, 92, 1141–1165. (b) Santamaria, J. In Photoinduced Electron Transfer;
Fox, M. A., Chanon, M., Eds.; Elsevier: New York, 1988; Part B.
(13) (a) Mizuno, K.; Ichinose, N.; Otsuji, Y. Chem. Lett. 1985, 14, 455–
458. (b) Mizuno, K.; Kamiyama, N.; Ichinose, N.; Otsuji, Y. Tetrahedron 1985,
41, 2207–2214. (c) Maeda, H.; Nakagawa, H.; Mizuno, K. Photochem. Photobiol.
Sci. 2003, 2, 1056–1058. (d) Maeda, H.; Miyamoto, H.; Mizuno, K. Chem. Lett.
2004, 33, 462–463.
(16) (a) Chiba, K.; Fukuda, M.; Kim, S.; Kitano, Y.; Tada, M. J. Org. Chem.
1999, 64, 7654–7656. (b) Chiba, K.; Kono, Y.; Kim, S.; Kitano, Y.; Tada, M.
Org. Electrochem. 2002, 9–12. (c) Horii, D.; Fuchigami, T.; Atobe, M. J. Am.
Chem. Soc. 2007, 129, 11692–11693. (d) Tajima, T.; Kurihara, H.; Fuchigami,
T. J. Am. Chem. Soc. 2007, 129, 6680–6681.
(17) Stewart, J. M.; Chang, C. H. J. Org. Chem. 1956, 21, 635–637.
8350 J. Org. Chem. Vol. 73, No. 21, 2008

Photoinduced Tandem Three-Component Coupling
CHART 1
mL)-water (1 mL) solution containing 1 (165 mg, 2.5 mmol), 2 (10.7
µL, 75 µmol), p-3 (3.2 mg, 25 µmol), phenanthrene (4.5 mg, 25 µmol),
and sodium carbonate (132 mg, 1.25 mmol). Argon gas was bubbled
through the solution for 5 min to reduce the amount of molecular
oxygen dissolved, and then the tube was sealed with a rubber septum.
After 20 h of irradiation by a 300-W high-pressure mercury lamp, the
reaction mixture was neutralized by the addition of dilute hydrochloric
acid and extracted with toluene-diethyl ether twice. The organic
extracts were combined and concentrated in vacuo giving a residue
(87% and 25% yield of p-4 (based on the amount of p-3 used) and 5
(based on the amount of 2 used), respectively, determined by 1H NMR
by using dibromomethane as an internal standard), which was
chromatographed on silica gel (ethyl acetate after toluene) to give a
crude product mixture. Further purification by HPLC (GPC column,
chloroform) gave pure p-4 (colorless oil) and 5 (colorless oil).
tion of nucleophilic anion species by use of weak base, which
can also be classified as an example of the active-site separation.
Three-Component Coupling Reaction of Polycyclic Cya-
noarenes. We have developed the coupling reaction using some
π-expanded polycyclic cyanoarenes.
1,4-Dicyanonaphthalene (10) does not undergo substitution
reaction but partially loses its aromaticity under a photoirra-
diation to afford tetralin derivative 11 in 26% yield (eq 5). Only
dual adduct 11 is obtained in the reaction. In this case, in contrast
to the observation for the reaction of 6, monoadduct is never
obtained even in the absence of phenanthrene. This can be
attributed to the highly reactive nature of R-cyanostyrene moiety
of the monoadduct.17 We assume that this reaction proceeds in
a similar mechanism to that of 3, except that the protonation
instead of cyanide elimination occurs on the anion intermediate
that corresponds to B-, due to the lower rearomatization energy
of the 1,2-dihydronaphthalene ring.
2-[trans-4-(4-Cyanophenyl)-1,1,4-trimethylpent-2-enyl]propane-
1
dinitrile (p-4): colorless oil; H NMR (CDCl3, 300 MHz) δ 1.39
(s, 6H), 1.44 (s, 6H), 3.56 (s, 1H), 5.50 (d, J ) 15.9 Hz, 1H), 5.87
(d, J ) 15.9 Hz, 1H), 7.42 (AA′XX′, J ) 8.7 Hz, 2H), 7.60
(AA′XX′, J ) 8.7 Hz, 2H) ppm; 13C NMR (CDCl3, 75 MHz) δ
25.6 (2C), 28.9 (2C), 36.1, 40.6, 41.6, 110.3, 111.9 (2C), 119.1,
127.2 (2C), 129.6, 132.3 (2C), 141.4, 153.3 ppm; MS (EI+) m/z
277 (4, M+), 212 (18, M+ - CH(CN)2), 182 (14), 170 (100, M+ -
CMe2CH(CN)2), 156 (18); HRMS (EI+) calcd for C18H19N3
277.1579, found 277.1572; IR (NaCl) 840, 2228 (-CN), 2252 (w,
-CN), 2972 cm-1
trans,trans-2,11-Dicyano-3,3,6,6,7,7,10,10-octamethyldodeca-4,8-
.
6
1
dienedinitrile (5): colorless blocks, mp 111-112 °C; H NMR
(CDCl3, 300 MHz) δ 1.00 (s, 12H), 1.36 (s, 12H), 3.61 (s, 2H),
5.36 (d, J ) 15.8 Hz, 2H), 5.80 (d, J ) 15.8 Hz, 2H) ppm; 13C
NMR (CDCl3, 75 MHz) δ 23.4 (4C), 25.9 (4C), 35.9 (2C), 40.8
(2C), 41.5 (2C), 112.3 (4C), 129.8 (2C), 140.1 (2C) ppm; MS (EI+)
m/z 175 (39, M+/2), 110 (100, M+/2 - CH(CN)2), 109 (35, M+/2
- CH2(CN)2), 95 (30, M+/2 - MeCH(CN)2); HRMS (CI+) calcd
for [C22H30N4 + H] 351.2549, found 351.2555; IR (NaCl) 800,
1019, 1093, 1261, 2238 (w, CN), 2252 (w, CN), 2968 cm-1. Anal.
Calcd for C22H30N4: C, 75.39; H, 8.63; N, 15.98. Found: C, 75.15;
H, 8.47; N, 15.86.
Determination of the Solubility of Sodium Carbonate in
Acetonitrile. Twenty milliliters of saturated solution of sodium
carbonate in acetonitrile at 18 °C was evaporated in vacuo, and to
the residue was added deionized water to give 20 mL of the aqueous
solution. An ICP-AES analysis was performed on the sample
solution, using 5 × 10-5 and 5 × 10-6 M aqueous solutions of
sodium carbonate as external standards (correlation coefficient:
0.9999) to determine the concentration of sodium ion as 3.6 × 10-5
M, hence the solubility was elucidated as 1.8 × 10-5 M (Ksp ) 2.3
× 10-14 M3).
On the other hand, neither substitution nor addition is
observed for the photoreaction of 9,10-dicyanoanthracene (12)
and 9-cyanophenanthrene (13), as in the case of m-3 (Chart 11).
The former is probably due to the steric hindrance among peri-
hydrogens, while the latter might be due to insufficient stability
of the corresponding anion intermediate.
Conclusions
A novel tandem three-component coupling reaction between
1, 2, and polycyanoarenes leading to selective and high-yielding
R-monoalkylation of 1 is developed. The reaction proceeds via
photo-NOCAS-type mechanism under mild, safe, and environ-
mentally friendly conditions such as ambient temperature,
absence of metals and halogens, and using a weak base. We
believe that the photoreaction will serve to broaden the synthetic
usefulness of the photochemical R-monoalkylation method of
1, which we have just reported.6
The reaction also represents a new type of cross-coupling
reaction that leads to aryl-cyano bond cleavage in the absence
of metals. In addition, the reaction is a rare example of
introducing carbon nucleophile in the PET reaction, except that
of cyanide ion.
Acknowledgment. We thank Dr. Masahiro Yasuda and Mr.
Seiji Nakashima at Osaka Prefecture University for helping us
to perform ICP-AES analysis, and Dr. Akihiro Nomoto at Osaka
Prefecture University for X-ray crystallographic analysis. This
work was partially supported by Grant-in-Aids for Scientific
Research on Priority Areas (420) (No. 16033252) and (444)
(No. 19020060), Scientific Research (C) (No. 20550049), and
JSPS Fellows (No. 20-4975) from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) of Japan.
1
Supporting Information Available: Spectral data and H
and 13C NMR spectra of the photoproducts (p-4, o-4, 5, 7-9,
11, and 14), and crystallographic data for 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
Experimental Section
Typical Experimental Procedure (entry 1 in Table 1). To a
Pyrex-made glass tube (1 cm φ) was added an acetonitrile (4
JO801624Q
J. Org. Chem. Vol. 73, No. 21, 2008 8351