Intramolecular polar addition reactions of active methylene moieties to aryl-substituted alkenes via photoinduced electron transfer

Article abstract of DOI:10.1016/j.tetlet.2010.07.165

The synthesis of cycloalkane derivatives with ring sizes of 5-7 was achieved in moderate yields by photoirradiation of aqueous acetonitrile solutions, containing compounds that consist of active methylene moieties tethered to aryl-substituted alkenes along with sodium hydroxide and 9-cyanophenanthrene. When the substrate contains ethyl cyanoacetate as an asymmetric active methylene moiety, the reaction proceeds in a highly diastereoselective manner.

Full text of DOI:10.1016/j.tetlet.2010.07.165

Tetrahedron Letters 51 (2010) 5537–5539
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular polar addition reactions of active methylene moieties
to aryl-substituted alkenes via photoinduced electron transfer
Maki Ohashi a, Keisuke Nakatani a, Hajime Maeda b, Kazuhiko Mizuno a,c,
⇑
a Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
b Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Ishikawa 980-8578, Japan
c The Research Institute for Molecular Electronic Devices (RIMED), Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of cycloalkane derivatives with ring sizes of 5–7 was achieved in moderate yields by phot-
oirradiation of aqueous acetonitrile solutions, containing compounds that consist of active methylene
moieties tethered to aryl-substituted alkenes along with sodium hydroxide and 9-cyanophenanthrene.
When the substrate contains ethyl cyanoacetate as an asymmetric active methylene moiety, the reaction
proceeds in a highly diastereoselective manner.
Received 10 June 2010
Revised 28 July 2010
Accepted 30 July 2010
Available online 5 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Ring-forming reactions are among the most interesting trans-
formations in organic chemistry, especially when they are incorpo-
rated as key steps in routes for the synthesis of complex natural
products. Although numerous methodologies have been developed
to generate cyclic structures,1 additional methods are needed to
complement and overcome some potentially weak features of
existing procedures.2
mation of the cyclopentane derivative 4a in 31% yield (Table 1,
entry 1). The corresponding inter-molecular adduct is not pro-
duced in this process. The structure of 4a was determined by using
1H and 13C NMR, MS, HRMS, and IR methods, along with a single-
crystal X-ray crystallographic analysis (Fig. S9 ). The reaction of
1a to generate 4a is the first example of a process that utilizes a
Several investigations have been carried out thus far to probe the
use of intramolecular photochemical polar addition (PPA) reactions
as ring-forming processes.3,4 However, the previous investigations
have focused only on substrates that contain carboxy and hydroxy
groups as nucleophiles. Cyclization reactions of these types of sub-
strates generate lactones and cyclic ethers. Prior to our current ef-
forts in this area, carbon nucleophiles had not been used in
intramolecularPPAreactionstoproducecarbocyclic-ringsystems.5,6
In the study described below, we explored intramolecular ver-
sions of PPA reactions of active methylene compounds whose
intermolecular counterparts were developed in a recent investiga-
tion.7 These studies have uncovered intramolecular reactions that
serve as a facile protocol to construct cycloalkane derivatives un-
der mild conditions (Eq. 1).
Table 1
Intra- and Inter-molecular PPA reactionsa
Entry
Substrate(s)
Alkene
Product
Yieldb (%)
Propanedinitrile
Ph
Ph
CN
1c
31
Ph
Ph
CN
NC
CN
1a
4a
Ph
Ph
Ph
Ph
NC
NC
CN
CN
2d
3d
4d
5d
66
38
22
0
CN
NC
NC
NC
Me
Ph
Ph
Ph
Me
CN
Ph
Ph
Ph
EWG1
Ph
Ph
hν
Ph
Ph
Me
Ph
Ph
Me
CN
sensitizer
base
NC
NC
CN
EWG2
ð1Þ
EWG1
EWG2
MeCN, H2O
rt
Me
Me
CN
Me
Ph
Ph
Ph
Ph
Me
CN
NC
Photoirradiation of an aqueous acetonitrile solution, containing
2-(5,5-diphenylpent-4-enyl)propanedinitrile (1a) and 9-cyanophe-
a
Conditions: 300-W high-pressure mercury lamp, Pyrex filter, alkene (75
l
mol),
propanedinitrile (2.5 mmol), 9-CP (25
H2O (1 mL), under Ar, rt, 20 h.
lmol), Na2CO3 (1.25 mmol), in MeCN (4 mL)-
nanthrene (9-CP) in the presence of sodium carbonate, leads to for-
b
Determined by 1H NMR analysis based on the amount of alkene used.
Substrate (1a): 75 lmol.
c
⇑
Corresponding author. Tel./fax: +81 72 254 9289.
E-mail address: mizuno@chem.osakafu-u.ac.jp (K. Mizuno).
d
Ref. 7.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.165

5538
M. Ohashi et al. / Tetrahedron Letters 51 (2010) 5537–5539
Table 2
It is interesting to compare the result of the intramolecular PPA
Intra-molecular PPA reactions of 1a, 2a–c, and 3aa
reaction with its intermolecular analogs.7,8 Inter-molecular photo-
reaction of 1,1-diphenylethene with propane-dinitrile (malononit-
rile) affords the PPA adduct in 66% yield (entry 2). The yield of this
reaction is lowered when alkene substrates that are sterically hin-
dered at the site of C–C bond formation are employed. A consider-
able decline in yield is also observed when methyl groups are
present in the alkene (entry 3) or propanedinitrile (entry 4) reac-
tants. When both of these substrates contain methyl substituents,
PPA reaction does not take place (entry 5). These observations
show that the reactivity profiles of the intra- and inter-molecular
PPA reactions are contrastingly different (compare entries 1 and
5). This finding indicates that connecting two reacting centers into
an intramolecular dyad causes a significant enhancement in the
efficiency of the PPA reaction.3,4
A study of the base dependence of the intramolecular PPA reac-
tion showed that heavier alkali metal carbonates enhance reaction
efficiency (Table 2, entries 1–5). The use of sodium hydroxide (en-
try 6) in contrast to potassium hydroxide (entry 7) affords the best
yield of 4a. Finally, photoproduct 4a is not formed when potassium
tert-butoxide is used as the base in dry acetonitrile (entry 8). Other
substrates also participate in the intramolecular PPA reaction. For
example, the cyclohexane derivative 5a is generated in high yield
(94%) in the intramolecular PPA reaction of the tethered malono-
nitrile 2a (entry 9 and Fig. S10 ).
Entry
Substrate
Base
Product
Yieldb (%)
1
2
3
4
5
1a
1a
1a
1a
1a
1a
1a
1a
2a
2b
Li2CO3
Na2CO3
K2CO3
Rb2CO3
Cs2CO3
NaOH
KOH
4a
4a
4a
4a
4a
4a
4a
4a
18
31
36
42
56
63
25
0
94
33
trace
0
6
7
8c
9
KOBut
NaOH
NaOH
5a
10
5b
epi-5b
5c
11
12
2c
3a
NaOH
NaOH
6a
25
a
Conditions: 300-W high-pressure mercury lamp, Pyrex filter, substrate
mol), 9-CP (25 mol), base (1.25 mmol), in MeCN (4 mL)-H2O (1 mL), under Ar,
(75
l
l
rt, 20 h.
Determined by 1H NMR analysis based on the amount of substrate used.
b
Unreacted starting alkenes 1–3 were almost recovered.
c
In dry MeCN.
The intramolecular addition of the cyanoacetate-containing
substrate 2b proceeds with high diastereoselectivity. While the
major isomer 5b is formed in 33% yield, only a trace of its epimer
epi-5b can be detected by using GC–MS analysis (entry 10). An
X-ray crystallographic analysis revealed that trans relationship ex-
ists between the diphenylmethyl and ethoxycarbonyl groups in 5b
and that these groups are located in equatorial positions of the
cyclohexane ring (Fig. 1).
Figure 1. ORTEP diagram for 5b.
The stereoselectivity of this process can be explained by consid-
ering steric interactions that exist between the ethoxy-carbonyl
and phenyl groups, and between the ethoxycarbonyl group and a
carbon nucleophile in an intramolecular PPA reaction. As such, it
represents a mild photochemical carbocyclic-ring forming method.
c-hydrogen atom of the developing six-membered ring (1,3-diaxial
EWG1
EWG2
CN
CN
Ph
Ph
interaction) in the transition states for intramolecular addition of
the enolate anion to the alkene-derived cation radical (Scheme 1).
In fact, these interactions appear to be the cause of the lack of reac-
tivity of the bis(methoxycarbonyl) derivative 2c (entry 11).
A cycloheptane ring can also be constructed by using intramo-
lecular PPA reaction of 3a, but the efficiency of this process is not
high (entry 12).
Ph
Ph
n
1a ; n = 1
2a ; n = 2
3a ; n = 3
2b ; EWG1 = CN, EWG2 = CO2Et
2c ; EWG1 = EWG2 = CO2Me
Ph
Ph
EWG1
Ph
Ph
Ph
Ph
Two mechanisms appear to be plausible for the intra-molecular
PPA reaction, both being initiated by deprotonation of the active
methylene moieties in substrate 1–3. One, following the normal
PPA pathway (Scheme 2),7–10 involves photoinduced electron
transfer (PET) from the alkene moiety to the excited singlet state
NC
CN
NC
EWG2
CN
6a
5a
; EWG1 = EWG2 = CN
4a
5b
5c
; EWG1 = CN, EWG2 = CO2Et
; EWG1 = EWG2 = CO2Me
1
*
of 9-CP ( 9-CP ) to afford an intramolecular radical cation–anion
CN
-
CN
EtO2C
Ph
EtO2C
+
Ph
H
H
5b
(33%)
2b
favor
CO2Et
H
CO2Et
-
NC
H
NC
Ph
Ph
+
H
epi-5b
(trace)
disfavor
Scheme 1. Steric relationship around the reaction site of 2b-derived intermediate.

M. Ohashi et al. / Tetrahedron Letters 51 (2010) 5537–5539
5539
Acknowledgments
+•
(CH2)n
Ph
Ph
(CH2)n
(CH )
2 n base
Ph
Ph
Ph
Ph
PET
This work was partially supported by Grant-in-Aids for Scien-
tific Research on Priority Areas (429) (16033252), Scientific
Research (B) (Nos. 15350026 and 20044027), JSPS Fellows (No.
20-4975), and the Cooperation for Innovative Technology and
Advanced Research in Evolutional Area (CITY AREA) program from
the Ministry of Education, Culture, Sports, Science and Technology
(MEXT) of Japan.
-
-
19-CP*
-•
EWG1 EWG2
9-CP
EWG1 EWG2
EWG1
EWG2
(CH2)n
hν
9-CP
Ph
-
Ph
(CH2)n
Ph
Ph
Ph
Ph
(CH2)n
H2O
BET
EWG1
EWG2
EWG1
EWG2
EWG1
EWG2
Scheme 2. Plausible mechanism (Path I): PET from the alkene moeity.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tetlet.2010.07.165.
(CH2)n
Ph
Ph
(CH )
2 n base
(CH2)n
Ph
Ph
Ph
Ph
PET
-
19-CP*
EWG2
-•
9-CP EWG1 EWG2
EWG1
EWG1
EWG2
hν
9-CP
References and notes
1. Fuji, K. Chem. Rev. 1993, 93, 2037–2066.
2. Sierra, M. A.; de la Torre, M. C. Dead Ends and Detours; Wiley-VCH: Weinheim,
2004. Chapter 8.
Scheme 3. Plausible mechanism (Path II): PET from the anion of active methylene
moeity.
3. (a) Gassman, P. G.; Bottorff, K. J. J. Am. Chem. Soc. 1987, 109, 7547–7548; (b)
Gassman, P. G.; De Silva, S. A. J. Am. Chem. Soc. 1991, 113, 9870–9872.
4. (a) Mizuno, K.; Tamai, T.; Nishiyama, T.; Tani, K.; Sawasaki, M.; Otsuji, Y. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2113–2115; (b) Nishiyama, Y.; Wada, T.; Asaoka,
S.; Mori, T.; McCarty, T. A.; Kraut, N. D.; Bright, F. V.; Inoue, Y. J. Am. Chem. Soc.
2008, 130, 7526–7527.
5. Yoon, U.-C.; Quillen, S. L.; Mariano, P. S.; Swanson, R.; Stavinoha, J. L.; Bay, E. J.
Am. Chem. Soc. 1983, 105, 1204–1218.
6. (a) Ishii, H.; Yamaoka, R.; Imai, Y.; Hirano, T.; Maki, S.; Niwa, H.; Hashizume, H.;
Iwasaki, F.; Ohashi, M. Tetrahedron Lett. 1998, 39, 9501–9504; (b) Ishii, H.; Imai,
Y.; Hirano, T.; Maki, S.; Niwa, H.; Ohashi, M. Tetrahedron Lett. 2000, 41, 6467–
6471.
7. (a) Ohashi, M.; Nakatani, K.; Maeda, H.; Mizuno, K. Org. Lett. 2008, 10, 2741–
2743; (b) Ohashi, M.; Nakatani, K.; Maeda, H.; Mizuno, K. J. Photochem.
Photobiol. A: Chem. 2010, 214, in press.
8. (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; (c) Ohashi,
M.; Nakatani, K.; Maeda, H.; Mizuno, K. J. Org. Chem. 2008, 73, 8348–8351; (d)
Ohashi, M.; Kano, Y.; Ikeda, H.; Mizuno, K. Tetrahedron 2010, 66, 3770–3774.
9. (a) Neunteufel, R. A.; Arnold, D. R. J. Am. Chem. Soc. 1973, 95, 4080–4081; (b)
Mangion, D.; Arnold, D. R. Acc. Chem. Res. 2002, 35, 297–304.
pair. Nucleophilic addition of the anion moiety to the radical cation
moiety then takes place to form a cyclic radical intermediate
that accepts an electron from 9-CPÅꢀ (back electron transfer; BET)
to form an anion which is protonated to form the carbocyclic prod-
uct. An alternative route resembles the mechanism for radical
cyclization (Scheme 3). In it, PET occurs from the anion of active
methylene moiety to the excited state of the sensitizer to yield a
radical that undergoes intramolecular addition to the alkene to af-
ford the same cyclic radical that serves as an intermediate in the
other mechanistic pathway. Since both PET pathways should be
highly exergonic (
D
Get = ꢀ0.98 and ꢀ2.96 eV when 1a is used)11–13
and both cyclization steps should take place smoothly, it is possible
that both are involved in this novel cyclization process.
In conclusion, a novel and facile synthetic method for the con-
struction of cycloalkane derivatives that relies on intramolecular
PPA or radical cyclization reactions of active methylene com-
pounds tethered to aryl-substituted alkenes has been developed
in this effort. When ethyl cyanoacetate is used as a pro-asymmetric
active methylene moiety, the reaction proceeds with a high degree
of diastereoselectivity. Moreover, the study has uncovered the first
examples in which carbon nucleophiles are employed in intramo-
lecular PPA reactions.
10. Yasuda, M.; Mizuno, K.. In Handbook of Photochemistry and Photobiology; Nalwa,
H. S., Ed.; American Scientific: Los Angeles, 2003; Vol. 2,. Chapter 8.
11. Oxidation potentials of 3a and (NC)2CHꢀ are +1.66 V and +0.55 V12 versus SCE,
and the reduction potential of 9-CP is ꢀ0.87 V versus SCE. Excited singlet state
energy of 9-CP is 3.45 eV.
equation (see Ref. 13).
DGet values were calculated by use of Rehm–Weller
12. (a) Niyazymbetov, M. E.; Rongfeng, Z.; Evans, D. H. J. Chem. Soc., Perkin Trans. 2
1996, 1957–1961; (b) Daasbjerg, K.; Knudsen, S. R.; Sonnichsen, K. N.; Andrade,
A. R.; Pedersen, S. U. Acta Chem. Scand. 1999, 53, 938–948.
13. Rehm, D.; Weller, A. Isr. J. Chem. 1970, 8, 259–271.
Finally, the new process might be synthetically useful since it
proceeds under relatively mild conditions.