A novel and efficient methodology for the C-C bond forming radical cyclization of hydrophobic substrates in water

Article abstract of DOI:10.1021/ol010014p

Matrix presented The combination of water-soluble radical initiator 2,2′-azobis[2-(2-imidazolin-2-yl)propane] (VA-061), water-soluble chain carrier 1-ethylpiperidine hypophosphite (EPHP), and surfactant cetyltrimethylammonium bromide (CTAB) was found to b

Full text of DOI:10.1021/ol010014p

ORGANIC
LETTERS
2001
Vol. 3, No. 8
1157-1160
A Novel and Efficient Methodology for
the C−C Bond Forming Radical
Cyclization of Hydrophobic Substrates
in Water
Yasuyuki Kita,* Hisanori Nambu, Namakkal G. Ramesh,†
Gopinathan Anilkumar, and Masato Matsugi
Graduate School of Pharmaceutical Sciences, Osaka UniVersity,
1-6, Yamada-oka, Suita, Osaka 565-0871, Japan
kita@phs.osaka-u.ac.jp
Received January 23, 2001
ABSTRACT
The combination of water-soluble radical initiator 2,2′-azobis[2-(2-imidazolin-2-yl)propane] (VA-061), water-soluble chain carrier 1-ethylpiperidine
hypophosphite (EPHP), and surfactant cetyltrimethylammonium bromide (CTAB) was found to be the most suitable condition for effective
radical cyclization in water for a variety of hydrophobic substrates.
Water has many potential advantages as a solvent for organic
reactions from the vantage point of its cost, safety, and
environmental concern.1 Recently, some attempts to achieve
organic reactions in aqueous media have been performed,
and consequently some successful examples have appeared
in the literature.2 The development of an efficient and
convenient synthetic methodology to accomplish C-C bond
formation in water is of paramount significance because of
heightened importance in green chemistry.
use of highly polar imine compounds, which can dissolve
easily in water. Some remarkable results along these lines
have been reported by Culbertson and Porter.5 In all these
reports, advantage has been taken of the hydrophilicity of
the respective substrates, which renders their easy solubility
in water, thereby facilitating a smooth C-C bond formation.
To the best of our knowledge, only isolated reports
restricted to some specific substrates are available for the
C-C bond forming radical reactions of hydrophobic sub-
strates in water. A general methodology for the C-C bond
forming radical reaction in water is highly desirable. In this
context, we wish to report the preliminary results of an
unprecedented C-C bond forming radical reaction of
An intramolecular radical cyclization in water has been
reported by Oshima et al.3 using â-iodocarbonyl compounds
as the substrate; however, increasing hydrophobicity of the
substrate tended to decrease the reactivity. Naito et al.4
recently reported a radical addition reaction in water by the
(3) (a) Yorimitsu, H.; Nakamura, T.; Shinokubo, H.; Oshima, K.; Omoto,
K.; Fujimoto, H. J. Am. Chem. Soc. 2000, 122, 11041. (b) Wakabayashi,
K.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. Bull. Chem. Soc. Jpn. 2000,
73, 2377. (c) Yorimitsu, H.; Nakamura, T.; Shinokubo, H.; Oshima, K. J.
Org. Chem. 1998, 63, 8604. (d) Nakamura, T.; Yorimitsu, H.; Shinokubo,
H.; Oshima, K. Synlett 1998, 1351. (e) Yorimitsu, H.; Wakabayashi, K.;
Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1999, 40, 519.
† Present address: Department of Chemistry, Indian Institute of Technol-
ogy, Hauz Khas, New Delhi 110 016, India.
(1) Organic Synthesis in Water; Grieco P. A., Ed.; Blackie Academic:
London, 1998.
(2) (a) Rai, R.; Collum, D. B. Tetrahedron Lett. 1994, 35, 6221. (b)
Yamazaki, O.; Togo, H.; Nogami, G.; Yokoyama, M. Bull. Chem. Soc.
Jpn. 1997, 70, 2519.
(4) Miyabe, H.; Ueda, M.; Naito, T. J. Org. Chem. 2000, 65, 5043.
(5) Culbertson, S. M.; Porter, N. A. J. Am. Chem. Soc. 1999, 121, 3791.
10.1021/ol010014p CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/27/2001

hydrophobic substrates in water using a novel and efficient
radical reaction system. Our strategy is based on the use of
a combination of a water-soluble radical initiator 2,2′-azobis-
[2-(2-imidazolin-2-yl)propane] (VA-061),6 water-soluble chain
carrier 1-ethylpiperidine hypophosphite (EPHP),7 and surf-
actant cetyltrimethylammonium bromide (CTAB).8
Table 1. Radical Cyclization Reaction Using Various Initiators
We presumed that a surfactant is essential to solubilize
the hydrophobic substrate in water, and with this in mind
we examined the radical cyclization of 1a using various
water-soluble azo-type initiators (Figure 1)6 in the presence
entry
initiator
time (h)
yield (trans:cis)a
1
2
3
4
5
6
7
8c
VA-061
VA-044
VA-080
VA-082
V-501
V-50
2
2.5
5
24
24
4
98% (55:45)
95% (50:50)
76% (50:50)
71% (50:50)
72% (51:49)
92% (51:49)
19% (57:43) [56%]b
50% (67:33) [46%]b
AlBN
Et3B
24
24
a The ratios were determined by 1H NMR. b Recovered starting material.
c Room temperature.
product was found to be low (Table 1, entry 8). On the other
hand, water-soluble initiators were found to be quite effective
in promoting the intramolecular cyclization of 1a. Remark-
ably, VA-061 was found to be the most suitable initiator
under these conditions (Table 1, entry 1), and thus the use
of VA-061 was explored further.
We next optimized for an expedient chain carrier for our
system containing VA-061 and CTAB (Table 2). Although
Figure 1. Water-Soluble Radical Initiators
Table 2. Effect of Various Chain Carrier
of water-soluble chain carrier (EPHP) and catalytic amount
of CTAB as the first chosen surfactant. The reaction did not
go to completion when the typical radical initiator AIBN
was used (Table 1, entry 7). While using Et3B,9 a known
radical initiator at low temperature, the yield of the desired
entry
chain carrier
none
time (h)
yield (trans:cis)a
(6) The water-soluble azo-type radical initiators used in our studies are
available from Wako Pure Chemical Industries, Ltd. Osaka, Japan. The
use of azo-type radical initiator (V-70) working at room temperature was
reported by us: Kita, Y.; Sano, A.; Yamaguchi, T.; Oka, M.; Gotanda, K.;
Matsugi, M. Tetrahedron Lett. 1997, 38, 3549. Kita, Y.; Gotanda, K.;
Murata, K.; Suemura, M.; Sano, A.; Yamaguchi, T.; Oka, M.; Matsugi, M.
Org. Process Res. DeV. 1998, 2, 250. Kita, Y.; Gotanda, K.; Ohira, C.;
Suemura, M.; Sano, A.; Matsugi, M. J. Org. Chem. 1999, 64, 6928 and
references therein.
1
2
3
24
2
6
no reaction
98% (55:45)
84% (78:22)
EPHP (10 equiv)
H3PO2 (10 equiv) +
NaHCO3 (10 equiv)
NaH2PO2 (10 equiv)
(TMS)3SiH (2 equiv)
4
5c
24
0.5
58% (78:22) [8%]b
94% (67:33)
(7) (a) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron
Lett. 1992, 33, 5709. (b) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C.
J. Org. Chem. 1993, 58, 6838. (c) Jang, D. O. Tetrahedron Lett. 1996, 37,
5367. (d) McCague, R.; Pritchard, R. G.; Stoodley, R. J.; Williamson, D.
S. Chem. Commun. 1998, 2691. (e) Tokuyama, H.; Yamashita, T.; Reding,
M. T.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791. (f)
Graham, S. R.; Murphy, J. A.; Coates, D. Tetrahedron Lett. 1999, 40, 2415.
(g) Graham, S. R.; Murphy, J. A.; Kennedy, A. R. J. Chem. Soc., Perkin
Trans. 1 1999, 3071. (h) Jang, D. O.; Song, S. H. Tetrahedron Lett. 2000,
41, 247. (i) Concepcion, G. M.; John, A. M.; Christopher, R. S. Tetrahedron
Lett. 2000, 41, 1833. (j) Yorimitsu, H.; Shinokubo, H.; Oshima, K. Chem.
Lett. 2000, 105.
(8) (a) Catalysis in Micellar and Macromolecular Systems; Fendler J.
H., Ed.; Academic Press: New York, 1998. (b) Tascioglu S. Tetrahedron
1996, 52, 11113. (c) Tohma, H.; Takizawa, S.; Watanabe, H.; Kita, Y.
Tetrahedron Lett. 1998, 39, 4547. (d) Tohma, H.; Takizawa, S.; Watanabe,
H.; Fukuoka, Y.; Maegawa, T.; Kita, Y. J. Org. Chem. 1999, 64, 3519.
(9) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991,
64, 403.
a The ratios were determined by 1H NMR. b Recovered starting material.
c VA-061 (0.5 equiv) was used.
the radical cyclization of 1a did not proceed at all in the
absence of chain carriers, we found that the addition of water-
soluble chain carriers afforded the expected cyclization
product in high yield within a short time. After screening a
series of chain carriers such as EPHP, tris(trimethylsilyl)-
silane [(TMS)3SiH],10 etc., we found that EPHP suits our
system the best. When (TMS)3SiH was used as the chain
(10) (a) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188. (b) Baguley,
P. A.; Walton, J. C. Angew. Chem., Int. Ed. Engl. 1998, 37, 3072.
1158
Org. Lett., Vol. 3, No. 8, 2001

carrier, the target product was obtained in good yield within
a short period of time; however, it required a tedious
procedure for the isolation of the desired product from the
byproduct derived from (TMS)3SiH.
reaction did not go to completion until 24 h (Table 3, entry
1). Thus, we discovered that the combination of VA-061,
EPHP, and CTAB is the most appropriate condition for
radical reactions in water for these substrates. It is worthy
to note that the concentration of CTAB used in our reactions
is within the range of micelle formation and therefore the
possibility of a micellar reaction cannot be ruled out.
However, at present, we do not have sufficient evidence to
prove this aspect.
We next investigated the additive effect of surfactants in
radical reactions in water. The characteristic effect of some
surfactants or phase transfer catalysts in radical cyclization
is apparent from Table 3. From these observations, we found
The utility and generality of this method was confirmed
by applying it to a series of hydrophobic substrates (1a-j).
In all cases, the intramolecular cyclization proceeded with
high efficiency and yield (Table 4). Notable is the fact that
the reaction showed low reactivity when no surfactant
(CTAB) was used.
Table 3. Effect of Various Surfactants
To test the scope and limitations of our methodology, we
subsequently investigated the radical cyclization strategy to
yield pyrrolidines, which are often present in natural
products. The allylamine 1k was subjected to the radical
reaction conditions in water at 80 °C, which afforded the
corresponding pyrrolidine 2k in 90% yield. Similar results
are summarized in Table 5. The attempted synthesis of the
unprotected amines to use as substrates in radical cyclization
met with unacceptable yields, probably as a result of the
inherent instability associated with these compounds. Thus,
we established that our method is also effective for the radical
cyclization in water to afford pyrrolidines (Table 5, entry
2). As expected, in the absence of the surfactant, the reaction
proceeded with decrease in reactivity (Table 5, entries 1 and
3). The following experimental results using a more hydro-
entry
additive (0.2 equiv)
time (h)
yield (trans:cis)a
1
2
2
4
5
none
CTAB
SDSc
Triton X-100d
Et4N+Br-
24
2
3.5
4
64% (74:26) [24%]b
98% (55:45)
98% (51:49)
98% (62:38)
85% (65:35) [7%]b
24
a The ratios were determined by 1H NMR. b Recovered starting material.
c SDS: sodium dodecyl sulfate. d Triton X-100: polyoxyethylene(10)
isooctylphenyl ether.
that CTAB is the most efficient additive for the radical
cyclization of 1a from the viewpoint of its rate acceleration
effect (Table 3, entry 2). In the absence of the additive, the
Table 4. Radical Cyclization Reaction Using VA-061, EPHP, and CTAB
a The ratios were determined by 1H NMR. b When CTAB was not used; reaction time, 24 h. c Obtained as a mixture of endo and exo (53:47). d VA-061
(0.5 equiv) was used. e Obtained as a mixture of endo and exo (76:24). f Obtained as a mixture of endo and exo (75:25) when CTAB was not used; reaction
time, 0.5 h. g NaHCO3 (10 equiv) was added. h VA-061 (1.5 equiv) was used.
Org. Lett., Vol. 3, No. 8, 2001
1159

tuning the amount of CTAB, the reactivity can be greatly
enhanced.
Table 5. Application to Other Hydrophobic Substrates
In conclusion, we have discovered that a combination of
VA-061, EPHP, and CTAB is an ideal reaction system to
accomplish radical cyclization in water. This method is an
elegant way to achieve C-C bond forming radical reactions
in water for various hydrophobic substrates. Further applica-
tion of this methodology is currently under active investiga-
tion in our laboratories.
entry
R
CTAB (equiv)
time (h)
yield (cis:trans)a
Acknowledgment. We thank Wako Pure Chemical
Industries, Ltd. for the generous supply of several water-
soluble azo-type initiators. N.G.R. and G.A. thank the Japan
Society for the Promotion of Science (JSPS) for postdoctoral
fellowships.
1
2
3
4
5
6
Ms
Ms
Ts
Ts
Ts
Ts
none
0.2
none
0.2
1
24
8
24
24
24
6
90% (72:28)
99% (72:28)
8% (53:47) [23%]b
46% (75:25) [21%]b
65% (75:25) [14%]b
87% (75:25)
2
Supporting Information Available: Experimental pro-
cedures and characterization for all compounds reported. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a The ratios were determined by 1H NMR. b Recovered starting material.
phobic substrate (1l) supported the apparent effectiveness
of the surfactant CTAB (Table 5, entries 4-6). Thus by
OL010014P
1160
Org. Lett., Vol. 3, No. 8, 2001