Photochemical monoalkylation of propanedinitrile by electron-rich alkenes

Article abstract of DOI:10.1021/ol800862x

(Chemical Equation Presented) The synthesis of monoalkylated propanedinitriles was achieved upon photoirradiation of MeCN/H₂O solutions containing propanedinitrile (1; malononitrile) and electron-rich alkenes in the presence of lithium carbonate and a catalytic amount of 9-cyanophenanthrene or redox-type photosensitizers (electron-mediating photosensitizers), through regioselective anti-Markovnikov photochemical polar addition of 1 into electronrich alkenes. With 2,5-dimethyl-2,4-hexadiene (2g) as an electron-rich alkene, propanedinitrile-incorporated dimer 4g was obtained.

Full text of DOI:10.1021/ol800862x

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2741-2743
Photochemical Monoalkylation of
Propanedinitrile by Electron-Rich
Alkenes
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 April 15, 2008
ABSTRACT
The synthesis of monoalkylated propanedinitriles was achieved upon photoirradiation of MeCN/H2O solutions containing propanedinitrile (1;
malononitrile) and electron-rich alkenes in the presence of lithium carbonate and a catalytic amount of 9-cyanophenanthrene or redox-type
photosensitizers (electron-mediating photosensitizers), through regioselective anti-Markovnikov photochemical polar addition of 1 into electron-
rich alkenes. With 2,5-dimethyl-2,4-hexadiene (2g) as an electron-rich alkene, propanedinitrile-incorporated dimer 4g was obtained.
Propanedinitrile (1; malononitrile) is one of the most versatile
reagents in organic chemistry as a consequence of the high
reactivity of both the methylene and cyano groups.1 This
substance has been employed extensively as a tool to extend
alkyl chains and to prepare heterocyclic and biologically
active compounds that have medical and industrial utility.
In particular, nucleophilic substitution reactions of alkyl
halides with the anion of 1, along with those of malonic
esters2 and other active methylene compounds,3 have been
widely employed as methods to link two building blocks in
the construction of intramolecular dyads.4,5 However, it is
often observed that overalkylation occurs in the first alky-
lation step employing 1 to give undesirable symmetrically
disubstituted products.4 Efforts have been made to overcome
this difficulty, including use of highly reactive reagents such
as strong bases and tight control of reaction conditions. In
addition, indirect approaches have been developed such as
Knoevenagel condensation6 followed by hydrogenation.7–9
(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.
(2) (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.
(4) D´ıez-Barra, E.; de la Hoz, A.; Moreno, A.; Sa´nchez-Verdu´, P.
Synthesis 1989, 391–393, and sited herein
.
(5) (a) Hutchins, R. O.; Maryanoff, B. E. Org. Synth. 1973, 53, 21–25.
(b) Mukae, H.; Maeda, H.; Mizuno, K. Angew. Chem., Int. Ed. 2006, 45,
(3) (a) Cope, A. C.; Holmes, H. L.; House, H. O. Org. React. 1957, 9,
107–331. (b) McMurry, J. E.; Musser, J. H. J. Org. Chem. 1975, 40, 2556–
2557. (c) Tiete, L.-F.; Kiedrowski, G. V. Tetrahedron Lett. 1981, 22, 219–
222. (d) Trost, B. M.; Conway, W. P.; Strege, P. F.; Dietsche, T. J. J. Am.
Chem. Soc. 1974, 96, 7165–7167.
6558-6560; Angew. Chem. 2006, 118, 6708-6710
.
(6) (a) Knoevenagel, E. Ber. Dtsch. Chem. Ges. 1898, 31, 730–737. (b)
Jones, G. Org. React. 1967, 15, 204–599. (c) Tietze, L. F.; Beifuss, U.
Org. Synth. 1993, 71, 167–174.
10.1021/ol800862x CCC: $40.75
Published on Web 06/07/2008
2008 American Chemical Society

In this paper, we report the first photochemical method
for direct alkylation of 1 to produce monoalkylated propane-
dinitrile derivatives 3 and 4 under mild conditions and in a
highly regioselective manner (eq 1).
in formation of dimer 4g in 52% yield (entry 7).12 Since the
1H and 13C NMR spectra of 4g are very simple and no
molecular ion peak is observed in the mass spectrum of 4g,
its structure was assigned by analogy with dimethoxy-
incorporated dimer12 and unambiguously by single-crystal
X-ray crystallographic analysis (Figure 1).
In exploratory studies, we have found that irradiation of
an aqueous acetonitrile solution containing 1, 1,1-diphe-
nylethene (2a), lithium carbonate and a catalytic amount of
9-cyanophenanthrene (9-CP) leads to anti-Markovnikov
addition to form the monoalkylated propanedinitrile 3a in
91% yield (Table 1, entry 1).10 Importantly, the formation
Figure 1. ORTEP diagram of 4g.
The reaction described above is a novel method for
alkylation of 1. It should find utility as a safe and environ-
mentally friendly synthetic method, since it proceeds under
mild conditions (ambient temperture and in the presence of
weak base) and, in contrast to the conventional SN2 alkyla-
tion, proceeds halogen-free. Besides, it is also the first
example of a process in which a nucleophilic carbon species
other than cyanide anion12b,13 is used in a photoinduced polar
addition.10,14
Further studies of the scope of this process revealed that
a use of heavier alkali ions results in lower yield of 3a (Table
2, entries 1-5). The photosensitizer can be changed from
9-CP to other electron-accepting sensitizers, e.g., 9,10-
dicyanoanthracene (9,10-DCA), with decrease of the yield
(entry 6). Also, phenanthrene (Phen) can be used as an
electron-donating photosensitizer together with strong electron-
accepting co-sensitizers, such as regioisomers of dicyanoben-
zene (DCB), in a so-called redox photosensitizing system
(entries 7-9).15
Table 1. Reaction of 1 with Various Alkenesa
entry alkene
R1
R2 R3 R4 product yield/b%
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
Ph
An
Ph
Ph
Ph
An
Ph Me
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
91
46
52
40
33
38
52
H
H
H
p-t-Bu-C6H4
Ph
Me2CdCH-
Me
H
2g
Me Me 4g
a Conditions: 300-W high-pressure mercury lamp, Pyrex filter, 1 (2.5
mmol), 2 (75 µmol), 9-CP (25 µmol), Li2CO3 (1.25 mmol), MeCN (4 mL),
H2O (1 mL), under Ar, rt, 20 h. b Determined by 1H NMR based on the
amount of 2 used.
In mechanistic investigations, we observed that deuterium
was incorporated into the benzylic position of 3a with a
d-content of 90% when deuterium oxide was used instead
of water in the mixed solvent system for reaction of 1a (entry
1, Table 1). This result clearly shows that protonation of the
anion intermediate proceeds at its benzylic position. Based
on this result, we propose that the reaction is promoted by
photoinduced electron transfer (PET) from 2 to the excited
singlet state of an electron-accepting photosensitizer (1Sens*)
of the dialkylated product was not observed. p-Methoxy- and
ꢀ-methylarylalkenes 2b and 2c, respectively, as well as
styrene and its p-tert-butyl and R-methyl derivatives (2d-f)
can also be used as alkenes in this photoaddition process to
yield the corresponding photoproducts 3b-f (entries 2-6).11
In contrast, use of diene 2g as an electron-rich alkene results
(7) Bogatskii, A. V.; Furman, D. B.; Colonditskaya, L. N. Zh. Org. Khim.
1966, 2, 5962; Chem. Abstr. 1966, 64, 14125.
(8) (a) Mizuno, K.; Ikeda, M.; Otsuji, Y. Chem. Lett. 1988, 1507–1510.
(b) Hayamizu, T.; Ikeda, M.; Maeda, H.; Mizuno, K. Org. Lett. 2001, 3,
1277–1280. (c) Hayamizu, T.; Maeda, H.; Mizuno, K. J. Org. Chem. 2004,
69, 4997–5004.
(12) (a) Mizuno, K.; Pac, C.; Sakurai, H. J. Am. Chem. Soc. 1974, 96,
2993–2994. (b) Ohashi, M.; Maeda, H.; Mizuno, K. Chem. Lett. 2006, 35,
482–483.
(9) Photochemical addition of hydrocarbons instead of hydrogen into
Knoevenagel products has been reported: Cardarelli, A. M.; Fagnoni, M.;
Mella, M.; Albini, A. J. Org. Chem. 2001, 66, 7320–7327.
(10) Neunteufel, R. A.; Arnold, D. R. J. Am. Chem. Soc. 1973, 95, 4080–
4081.
(13) (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) Kitagawa, F.; Murase, M.; Kitamura, N. Chem.
Lett. 2001, 786–787
.
(14) Yasuda, M.; Mizuno, K. In Handbook of Photochemistry and
Photobiology; Nalwa, H. S., Ed.; American Scientific Publishers: Los
Angeles, CA, 2003; Vol. 2, Chapter 8.
(11) Enantioselective addition of alcohols into 2c has been reported:
(a) Inoue, Y.; Okano, T.; Yamasaki, N.; Tai, A. J. Chem. Soc., Chem.
Commun. 1993, 718–720. (b) Asaoka, S.; Kitazawa, T.; Wada, T.; Inoue,
Y. J. Am. Chem. Soc. 1999, 121, 8486–8498.
(15) Majima, T.; Pac, C.; Nakasone, A.; Sakurai, H. J. Am. Chem. Soc.
1981, 103, 4499–4508.
2742
Org. Lett., Vol. 10, No. 13, 2008

Scheme 1. Plausible Mechanism for the Formation of 3 and 4g
to build up a higher steady-state concentration, which enables
Table 2. Reaction of 1 with 2a under Various Conditionsa
it to dimerize. The dimerization occurs regioselectively at
its terminal position to form 4g, a result that correlates with
the relative stabilities of the three possible dimers. The anion
A- derived from 2g dissociates spontaneously (∆Gq ∼ 2 kcal/
mol by HF/3-21G) to form the starting materials (i.e., anion
of 1 and 2g). In the redox-photosensitized process, Phen acts
as an electron mediator between alkene and the co-
sensitizer16 and the resulting radical ion pair reacts in a
similar manner as described above.
entry
sensitizer(s)
base
yield/b%
1
2
3
4
5
6
7
8
9
9-CP
9-CP
9-CP
9-CP
Li2CO3
Na2CO3
K2CO3
Rb2CO3
Cs2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
91
66
68
23
15
27
71
60
44
9-CP
In conclusion, a novel, safe and environmentally friendly
synthetic method for the direct and mild monoalkylation of
propanedinitrile, using photoinduced polar addition with
electron-rich alkenes, has been developed. This represents
the first example in which a carbon nucleophile, other than
cyanide anion, is used in a photoinduced polar addition
process.
9,10-DCA
Phen, o-DCB
Phen, m-DCB
Phen, p-DCB
a Conditions: 300-W high-pressure mercury lamp, Pyrex filter, 1 (2.5
mmol), 2a (75 µmol), sensitizer(s) (25 µmol each), base (1.25 mmol), MeCN
b
1
(4 mL), H2O (1 mL), under Ar, rt, 20 h. Determined by H NMR based
on the amount of 2a used.
Acknowledgment. We thank Dr. Akihiro Nomoto at
Osaka Prefecture University for his contribution on X-ray
crystallographic analysis. This work was partially supported
by Grant-in-Aids for Scientific Research on Priority Areas
(420) (No. 16033252), Scientific Research (B) (No. 15350026),
and JSPS Fellows (No. 20-4975) from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT)
of Japan.
(Scheme 1). This affords the radical cations of 2a-g, which
react with the anion of 1 to form benzylic radical intermedi-
ates A•.16 In the case of mono-olefins (e.g., 2a), back electron
transfer (BET) from the sensitizer radical anion (e.g., 9-CP•-)
to A• is highly exothermic (e.g., -33.4 kcal/mol by
(U)B3LYP/6-31G*) and fast; the resulting anions A- are
protonated to give the anti-Markovnikov adducts 3a-f.
Dimerization of A• does not occur owing to steric hindrance
and low steady-state concentration of the radical. On the other
hand, allylic radical A• derived from a diene is stable enough
Supporting Information Available: Typical experimental
procedure, characterization data for 3a-f and 4g, and
crystallographic data for 3a and 4g. This material is available
free of charge via Internet at http://pubs.acs.org.
(16) An alternative pathway might involve photoinduced electron transfer
from the anion derived from 1 to the excited singlet state of the sensitizer,
followed by coupling of the resulting radical with 2 to form A•.
OL800862X
Org. Lett., Vol. 10, No. 13, 2008
2743