Iron-catalyzed redox radical cyclizations of 1,6-dienes and enynes

Article abstract of DOI:10.1021/ol902562j

Chemical Equation Presented Treatment of 1,6-dienes and enynes with FeCl₃ or Fe(Pc) in the presence of NaBH₄ and air or O₂ causes radical cyclization to give fivemembered carbo or heterocyclic compounds, into which a halogen atom or hydroxyl group was introduced

Full text of DOI:10.1021/ol902562j

ORGANIC
LETTERS
2010
Vol. 12, No. 1
112-115
Iron-Catalyzed Redox Radical
Cyclizations of 1,6-Dienes and Enynes
Tsuyoshi Taniguchi, Naoya Goto, Asami Nishibata, and Hiroyuki Ishibashi*
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health
Sciences, Kanazawa UniVersity, Kakuma-machi, Kanazawa 920-1192, Japan
isibasi@p.kanazawa-u.ac.jp
Received November 4, 2009
ABSTRACT
Treatment of 1,6-dienes and enynes with FeCl3 or Fe(Pc) in the presence of NaBH4 and air or O2 causes radical cyclization to give five-
membered carbo or heterocyclic compounds, into which a halogen atom or hydroxyl group was introduced.
Radical cyclizations have been powerful tools for the
construction of cyclic systems in synthetic chemistry.1
Radical reactions have generally been performed by treatment
Scheme 1. Cobalt- or Iron-Catalyzed Oxygenation of Olefins
of alkyl or aryl halides or chalcogenides with a hydrogen
donor such as Bu3SnH in the presence of a radical initiator
such as AIBN [azobis(isobutyronitrile)].
There are, however, some disadvantages due to the use
of toxic reagents and the difficulty in product purification.
Therefore, tin-free radical reactions have been developed in
recent years.2
Interest has recently been shown in iron as a low-toxicity
and inexpensive substitute for rare metals such as palladium,
and many efficient iron-catalyzed reactions have been
reported.3 In 1984, Okamoto reported the hydration of
presence of NaBH4,7 and Boger and co-workers reported the
styrenes using cobalt or iron complexes and NaBH4 under
air (Scheme 1, eq 1).4-6 Quite recently, Beller and co-
workers reported the synthesis of oximes from styrenes using
a catalytic amount of iron phtalocyanine [Fe(Pc)] in the
hydration of trisubstitute olefins of vinblastine and ꢀ-cit-
ronellol using excess iron salts and NaBH4 under air.8 A
radical mechanism has been proposed for these reactions.4,5,8
Nevertheless, an application of these methods using iron
compounds and NaBH4 to radical cyclizations has never
been explored.9 Herein, we report iron-catalyzed redox
(1) For reviews, see: (a) Renaud, P.; Sibi, M. P. Radical in Organic
Synthesis; Wiley-VCH: Weinheim, 2001. (b) Gansa¨uer, A., Ed.; Topics
Current Chemistry; Radicals in Synthesis I and II; Springer: Berlin; 2006;
Vols. 263 and 264.
(2) For selected recent examples, see: (a) Schaffner, A.-P.; Darmency,
V.; Renaud, P. Angew. Chem., Int. Ed. 2006, 45, 5847. (b) Medeiros, M. R.;
Schacherer, L. N.; Spiegel, D. A.; Wood, J. L. Org. Lett. 2007, 9, 4427. (c)
Smith, D. M.; Pulling, M. E.; Norton, J. R. J. Am. Chem. Soc. 2007, 129,
770. (d) Gansa¨uer, A.; Fan, C.-A.; Piestert, F. J. Am. Chem. Soc. 2008,
130, 6916. (e) Ueng, S.-H.; Makhlouf Brahmi, M.; Derat, E.; Fensterbank,
L.; Lacoˆte, E.; Malacria, M.; Curran, D. P. J. Am. Chem. Soc. 2008, 130,
10082. (f) Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2008, 10, 3279. (g)
Akindele, T.; Yamada, K.; Tomioka, K. Acc. Chem. Res. 2009, 42, 345.
(h) Friestad, G. K.; Banerjee, K. Org. Lett. 2009, 11, 1095.
(3) For reviews, see: (a) Iron Catalysis in Organic Chemistry; Plietker,
B., Ed.; Wiley-VCH: Weinheim, 2008. (b) Bolm, C.; Legros, J.; Le Paih,
J.; Zani, L. Chem. ReV. 2004, 104, 6217. (c) Fu¨rstner, A.; Martin, R. Chem.
Lett. 2005, 34, 624. (d) Correa, A.; Manchen˜o, O. G.; Bolm, C. Chem.
Soc. ReV. 2008, 37, 1108. (e) Enthaler, S.; Junge, K.; Beller, M. Angew.
Chem., Int. Ed. 2008, 47, 3317. (f) Sherry, B. D.; Fu¨rstner, A. Acc. Chem.
Res. 2008, 47, 1500. (g) Correa, A.; Garc´ıa Manchen˜o, O.; Bolm, C. Chem.
Soc. ReV. 2008, 37, 1108. (h) Fu¨rstner, A. Angew. Chem., Int. Ed. 2009,
48, 1364.
(4) Okamoto, T.; Oka, S. J. Org. Chem. 1984, 49, 1589.
10.1021/ol902562j  2010 American Chemical Society
Published on Web 12/02/2009

Table 1. Iron-Catalyzed Radical Cyclization of 1a
yield (%)a b
,
entry
[Fe] (equiv)
[BH4]- (equiv)
solvent
gas
temp (°C)
time (h)
2a
3a
1
2
3
4
5
6
7
8
9
FeCl3 (1.2)
FeCl3 (1.2)
FeCl3 (1.2)
FeCl3 (1.2)
FeCl3 (1.2)
FeCl3 (1.2)
Fe(NO3)3 (1.2)
Fe(Pc) (0.1)
Fe(Pc) (0.1)
b
NaBH4 (1.5)
NaBH4 (1.5)
NaBH4 (1.5)
NaBH4 (1.5)
LiBH4 (1.5)
NaBH4 (1.5)
NaBH4 (1.5)
NaBH4 (3.0)
NaBH4 (3.0)
THF
THF
THF
THF
THF
THF
THF
THF
EtOH
1
Air
N2
Air
O2
O2
O2
O2
O2
O2
0 f rt
0 f rt
-45
-45
-45
-78 f rt
-78 f rt
rt
0.5
0.5
4
2
5
2
2
1
3
68
18
48
4
18
15
17
3
28
54
55
58
44
rt
65
a Yield of isolated products. Diastereomer ratio was determined by H NMR analysis.
radical cyclizations of 1,6-dienes using NaBH4 (Scheme
1, eq 2).10
(0.01-0.5 M) and the use of excess reagents also gave no
improved result. The reaction under N2 atmosphere instead
of air resulted in a significant lower yield of products. (Table
1, entry 2). At the lower reaction temperature, the increased
quantity of hydroxy product 3a was observed (Table 1, entry
3). It was found that FeCl3-mediated reaction under O2
atmosphere in lower temperature gave 3a as the major
product (Table 1, entries 4-6). The use of LiBH4 instead of
NaBH4 gave a similar result (Table 1, entry 5). The use of
Fe(NO3)3 instead of FeCl3 gave only 3a (Table 1, entry 7).
When a catalytic amount of iron phtalocyanine [Fe(Pc)] was
used in EtOH under O2 atmosphere at room temperature,
only 3a was obtained in good yield (Table 1, entry 9). Fe(Pc)
showed catalytic activity, whereas FeCl3 showed no catalytic
activity.13 Therefore, we concluded that FeCl3/NaBH4 in THF
under air gives chlorinated cyclization product 2a and that
Fe(Pc) (cat.)/NaBH4 in EtOH under O2 atmosphere affords
hydroxy cyclization product 3a.
Next, radical cyclizations of several 1,6-dienes 1b-g using
FeCl3 (method A) and Fe(Pc) (method B) were examined
(Table 2). The precursor 1b bearing a prenyl group gave
chlorinated cyclization product 2b by method A, whereas
no cyclization product was obtained by method B (Table 2,
entries 2). Since the hydrated product of the trisubsutituted
olefin of 1b was detected, the trisubsutituted olefin might
be more reactive than the terminal olefin in the condition
using method B. Reactions of precursors 1c and 1d bearing
a cyclohexene group or 2-methylallyl group gave chlorinated
products 2c, 2c′ and 2d, 2d′ by method A and hydroxy
Treatment of 1,6-diene 1a with 1.2 equiv of FeCl3 and
NaBH4 (1.5 equiv) in THF (0.1 M) under air at room
temperature gave chlorinated cyclization product 2a (68%)
along with a small amout of hydroxy cyclization product 3a
(17%) (Table 1, entry 1).11,12 When Et2O, MeCN, or MeOH
was used as a solvent, very lower yield of product was
observed. The change of concentration of a substrate
(5) Co- or Mn-catalyzed hydration reactions of olefins using O2 and
silanes have been reported by Mukaiyama and co-workers; see: (a)
Mukaiyama, T.; Isayama, S.; Inoki, S.; Kato, K.; Yamada, T.; Takai, T.
Chem. Lett. 1989, 449. (b) Inoki, S.; Kato, K.; Takai, T.; Isayama, S.;
Yamada, T.; Mukaiyama, T. Chem. Lett. 1989, 515. (c) Isayama, S.;
Mukaiyama, T. Chem. Lett. 1989, 1071. (d) Isayama, S.; Mukaiyama, T.
Chem. Lett. 1989, 569. (e) Isayama, S.; Mukaiyama, T. Chem. Lett. 1989,
573. (f) Kato, K.; Yamada, T.; Takai, T.; Inoki, S.; Isayama, S. Bull. Chem.
Soc. Jpn. 1990, 63, 179. (g) Isayama, S. Bull. Chem. Soc. Jpn. 1990, 63,
1305.
(6) Recently, Carreira and co-workers have reported the cobalt-catalyzed
functionalization of inactive alkenes; see: (a) Waser, J.; Nambu, H.; Carreira,
E. M. J. Am. Chem. Soc. 2005, 127, 8294. (b) Waser, J.; Gonza´lez-Go´mez,
J. C.; Nambu, H.; Huber, P.; Carreira, E. M. Org. Lett. 2005, 7, 4249. (c)
Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2006,
128, 11693. (d) Gaspar, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2007,
46, 4519. (e) Gaspar, B.; Waser, J.; Carreira, E. M. Synthesis 2007, 3839.
(f) Gaspar, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 5758.
(7) Prateeptongkum, S.; Jovel, I.; Jackstell, R.; Vogl, N.; Weckbecker,
C.; Beller, M. Chem. Commun. 2009, 1990.
(8) Ishikawa, H.; Colby, D. A.; Seto, S.; Va, P.; Tam, A.; Kakei, H.;
Rayl, T. J.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2009, 131, 4904.
(9) For examples of iron-mediated radical cyclizations, see: (a) Cabri,
W.; Borghi, D.; Arlandini, E.; Sbraletta, P.; Bedeschi, A. Tetrahedron 1993,
49, 6837. (b) Booker-Milburn, K. I.; Thompson, D. F. J. Chem. Soc., Perkin
Trans. 1 1995, 2315. (c) Booker-Milburn, K. I.; Barker, A.; Brailsford,
W.; Cox, B.; Mansley, T. E. Tetrahedron 1998, 54, 15321. (d) Jahn, P.;
Hartmann, P. Chem. Commun. 1998, 209. (e) Bach, T.; Schlummer, B.;
Harms, K. Chem. Commun. 2000, 287. (f) Booker-Milburn, K. I.; Jones,
J. L.; Sibley, G. E. M.; Cox, R.; Meadows, J. Org. Lett. 2003, 5, 1107.
(10) For selected recent examples of radical cyclizations of 1,6-dienes,
see: (a) Ueda, M.; Miyabe, H.; Nishimura, A.; Miyata, O.; Takemoto, Y.;
Naito, T. Org. Lett. 2003, 5, 3835. (b) Schmidt, B.; Pohler, M.; Costisella,
B. J. Org. Chem. 2004, 69, 1421. (c) James, P.; Schenk, K.; Landais, Y. J.
Org. Chem. 2006, 71, 3630. (d) Hirai, T.; Han, L.-B. Org. Lett. 2007, 9,
53. (e) Mantrand, N.; Renaud, P. Tetrahedron 2008, 64, 11860. (f) Sa´nchez,
E. M.; Arteaga, J. F.; Domingo, V.; Qu´ılez del Moral, J. F.; Mar Herrador,
M.; Barrero, A. F. Tetrahedron 2008, 64, 5111.
(11) cis-Isomers for 2a and 3a were assumed to be major products, since
radical cyclizations of 1,6-dienes generally afforded cis products; see: Tripp,
J. C.; Schiesser, C. H.; Curran, D. P. J. Am. Chem. Soc. 2006, 127, 5518.
(12) In the reaction of 1a, simple hydrochlorinated or hydrated product
of olefin was also detected by NMR analysis of the crude product.
(13) It has been reported that the reaction of FeCl3 with LiBH4 or NaBH4
gives iron(II) borohydride [Fe(BH4)2]; see: (a) Schaeffer, G. W.; Roscoe,
J. S.; Stewart, A. C. J. Am. Chem. Soc. 1956, 78, 729. (b) Glavee, G. N.;
Klabunde, K. J.; Sorensen, C. M.; Hadjipanayis, G. C. Inorg. Chem. 1995,
34, 28.
Org. Lett., Vol. 12, No. 1, 2010
113

Table 2. Iron-Catalyzed Radical Cyclization of Various
1,6-Dienes
Table 3. Iron-Catalyzed Radical Cyclization of Eneynes 4a-d
entry
R
time (h)
yield (%)a
ratiob
1
2
3
4
Ph
a
b
c
4.5
1
0.5
1
43
53
65
57
85:15
75:25
75:25
60:40
TMS
TBS
TIPS
d
a Yield of isolated products. b Ratio was determined by 1H NMR analysis.
by the fact that bis-sulfone derivative 1f gave chlorinated
product 2f and hydroxy product 3f in excellent yields (Table
2, entry 6). The reaction of diallyl ether (1g) also gave
chlorinated product 2g and hydroxy product 3g in good
yields, respectively (Table 2, entry 7). The cyclization
reactions of several eneyne compounds were also exam-
ined.15-17 As shown in Table 3, treatment of enyne
compounds 4a-d bearing phenyl or silyl groups on alkyne
with FeCl3 and NaBH4 under air resulted in 5-exo-dig
cyclization to give vinyl chlorides 5a-d in moderate yields,
respectively.18,19
A brominated or iodinated cyclization compound was also
accessible by using appropriate radical trapping reagents.
Treatment of 1a with FeBr3 and NaBH4 under air gave
brominated cyclization product 6a (Scheme 2, eq 1), and
the addition of excess diiodoethane to the mixture of FeCl3/
NaBH4 gave iodinated cyclization prouduct 7a (Scheme 2,
eq 2).
A plausible mechanism for the reaction is shown in
Scheme 3. Reaction of 1,6-diene 1a may be initiated by
generation of σ-alkyliron(III) complex 8. Fe-C bond cleav-
age of complex 8 by O2 followed by cyclization of the
resultant radical intermediate 9 gives the new radical 10.
When FeCl3 is employed as an iron source, the addition of
(14) When Et3SiH was used as
occurred.
(15) For a recent review of catalytic enyne cyclizations, see: Michelet,
V.; Toullec, P. Y.; Geneˆt, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268
a hydride source, no reaction
.
(16) Indium-madiated reductive radical cyclizations of enynes have been
reported; see: (a) Takami, K.; Mikami, S.; Yorimitsu, H.; Shinokubo, H.;
Oshima, K. J. Org. Chem. 2003, 68, 6627. (b) Miura, K.; Fujisawa, N.;
Hosomi, A. J. Org. Chem. 2004, 69, 2427. (c) Hayashi, N.; Shibata, I.;
Baba, A. Org. Lett. 2004, 6, 4981. (d) Hayashi, N.; Shibata, I.; Baba, A.
a Yield of isolated products. b Ratio was determined by 1H NMR analysis.
Determined by H NMR analysis of a crude product.
c
1
Org. Lett. 2005, 7, 3093
.
(17) Quite recently, the iron-catalyzed reductive cyclization of 1,6-enynes
and diynes has been reported; see: (a) Sylvester, K. T.; Chirik, P. J. J. Am.
products 3c, 3c′, and 3d by method B, respectively (Table
2, entries 3 and 4). In terms of the reactions of these
unsymmetrical 1,6-dienes, chemoselectivity in functional-
ization of olefins was observed. Dimethyl malonate derivative
1e gave chlorinated product 2e in moderate yield (method
A), but hydroxy product 3e was obtained in very low yield
(method B) (Table 2, entry 5). It was assumed that the low
yield of 3e was due to the instability of ester moieties under
the reaction conditions.14 This consideration was supported
Chem. Soc. 2009, 131, 8772
.
(18) For recent examples of the synthesis of vinyl halides using iron
catalyst, see: (a) Miranda, P. O.; Diaz, D. D.; Padro´n, J. I.; Bermejo, J.;
Mart´ın, V. S. Org. Lett. 2003, 11, 1979. (b) Miranda, P. O.; D´ıaz, D. D.;
Padro´n, J. I.; Ram´ırez, M. A.; Mart´ın, V. S. J. Org. Chem. 2005, 70, 57.
(c) Carballo, R. M.; Ram´ırez, M. A.; Rodr´ıguez, M. L.; Mart´ın, V. S.;
Padro´n, J. I. Org. Lett. 2006, 8, 3837. (d) Miranda, P. O.; Carballo, R. M.;
Martin, V. S.; Padro´n, J. I. Org. Lett. 2009, 11, 357. (e) Xu, T.; Yu, Z.;
Wang, L. Org. Lett. 2009, 11, 2113. (f) Cantagrel, G.; Carne´-Carnavalet,
B.; Meyer, C.; Cossy, J. Org. Lett. 2009, 11, 4262
(19) The reaction of enyne substrates using method B gave a complex
mixture of products.
.
114
Org. Lett., Vol. 12, No. 1, 2010

Scheme 2. Introduction of Bromine and Iodine Atoms
Scheme 3. Plausible Mechanism
a chlorine atom to the radical 10 gives chlorinated product
2a.9 On the other hand, in the case of using a catalytic Fe(Pc),
the radical 10 was trapped by O2 to give peroxide radical
11. Formation of Fe(Pc)-peroxide complex 12 followed by
reduction by NaBH4 gives hydroxy product 3a.20
In summary, we have developed efficient iron-catalyzed
redox radical cyclizations of 1,6-dienes to give functionalized
cyclic compounds. The present reaction system consists of
inexpensive and environmentally friendly reagents, and the
experimental procedure is simple and safe. Further studies
directed toward application of these iron-catalyzed redox
radical cyclizations to the reactions of various precursors are
currently underway in our laboratory.
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology of Japan.
Supporting Information Available: Expermental detail
and spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(20) Sugimori, T.; Horike, S.-i.; Tsumura, S.; Honda, M.; Kasuga, K.
Inorg. Chim. Acta 1998, 283, 275.
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