Titanocene(III) mediated 8-endo radical cyclizations for the synthesis of eight-membered cyclic ethers

Article abstract of DOI:10.1016/j.tetlet.2005.12.131

Titanocene(III) chloride (Cp₂TiCl) mediated 8-endo radical cyclizations towards the synthesis of eight-membered cyclic ethers have been described. Titanocene(III) chloride was prepared in situ from commercially available titanocene dichloride (Cp₂TiCl₂) and activated zinc dust in THF.

Full text of DOI:10.1016/j.tetlet.2005.12.131

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1599–1601
Titanocene(III) mediated 8-endo radical cyclizations for
the synthesis of eight-membered cyclic ethers
Samir Kumar Mandal and Subhas Chandra Roy*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 17 November 2005; revised 12 December 2005; accepted 22 December 2005
Available online 20 January 2006
Abstract—Titanocene(III) chloride (Cp2TiCl) mediated 8-endo radical cyclizations towards the synthesis of eight-membered cyclic
ethers have been described. Titanocene(III) chloride was prepared in situ from commercially available titanocene dichloride
(Cp2TiCl2) and activated zinc dust in THF.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The synthesis of medium and large-sized ring ethers is a
highly challenging problem to organic chemists due to
their widespread occurrence in natural products such
as brevetoxin-A, ciguatoxin, prelaureatin, laurallene,
helianane, heliannuol and radulanin-E. Several meth-
ods1 have been developed for constructing medium-
sized rings including ring-closing metathesis (RCM).
Radical cyclization reactions have become an invaluable
tool in synthetic organic chemistry, especially in the syn-
thesis of complex natural products, due to the mildness
of their generation and predictable behaviour in many
organic transformations.2 In continuation of our study3
on titanocene(III) chloride (Cp2TiCl) mediated radical
cyclization reactions for the synthesis of five- and six-
membered oxygen heterocycles and related natural
products, we report here, for the first time, titano-
cene(III) mediated 8-endo radical cyclizations towards
the synthesis of eight-membered ethers in good yields.
Cp2TiCl was prepared4 in situ from commercially avail-
able Cp2TiCl2 and activated zinc dust in THF. When we
had almost completed our study, a report appeared5 on
7-endo radical cyclizations catalyzed by titanocene(III).
Thus, 2-allyl phenol 1a, prepared from allyl phenyl ether
via Claisen rearrangement, was treated with propargyl
bromide in the presence of K2CO3 to yield 2a in excel-
lent yield (Scheme 1). The propargyl ether 2a on treat-
ment with m-CPBA in CH2Cl2 afforded the epoxide 3a
in excellent yield. The epoxide 3a on treatment with
K2CO3,
Br
OH
O
O
m-CPBA
O
acetone, reflux, 4 h
CH2Cl3, rt, overnight
R
R
R
1a, R = H
1b, R = Me
3a, R = H (93%)
3b, R = Me (90%)
2a, R = H (93%)
2b, R = Me (90%)
O
O
Cp2TiCl,
THF, rt
+
+
another unidentified product (18-20%)
OH
R
R
OH
5a, R = H (12%)
5b, R = Me (9%)
4a, R = H (52%)
4b, R = Me (58%)
Scheme 1.
Keywords: Titanocene(III) chloride; 8-endo Radical cyclization; Cyclic ethers.
*
Corresponding author. Tel./fax: +91 33 2473 4971; e-mail: ocscr@iacs.res.in
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.131

1600
S. K. Mandal, S. C. Roy / Tetrahedron Letters 47 (2006) 1599–1601
O
Cl
OH
Cp2TiCl,
THF, rt
O
O
NaOEt, EtOH
rt, 1 h
72%
1a
6
OH
O
OH
O
+
+
two other unidentified products (25%)
7 (44%)
8 (11%)
Scheme 2.
Cp2TiCl in THF under argon afforded6 the eight-mem-
bered ether 4a in moderate yield (52%) along with the
reduced product 5a (9–12%) and an unidentified product
(18–20%). The methyl substituted derivative 4b (58%)
was prepared in a similar manner.
N.; Khan, T. A.; Scho¨nebeck, F.; Murphy, J. A.; Payne, A.
H.; Williams, A. C. Tetrahedron Lett. 2005, 46, 4027, and
references cited therein; (o) Pirrung, F. O. H.; Hiemstra, H.;
Speckamp, W. N.; Kaptein, B.; Schoemaker, H. E. Tetra-
hedron 1994, 50, 12415, and references cited therein; (p)
Lee, E.; Yoon, C. H.; Lee, T. H.; Kim, S. Y.; Ha, T. J.;
Sung, Y.-S.; Park, S.-H.; Lee, S. J. Am. Chem. Soc. 1998,
120, 7469.
On the other hand, 2-allyl phenol 1a was transformed
into 6 in a single-step using epichlorohydrin (Scheme
2). Reductive opening of the epoxide 6 using Cp2TiCl
in THF under argon afforded the eight-membered ether
7 (44%) along with the reduced product 8 (11%) and two
other unidentified products (25%).
2. (a) Giese, B. Radicals in Organic Synthesis: Formation of
Carbon–Carbon Bonds; Pergamon Press: Oxford, 1986; (b)
Motherwell, W. B.; Crich, D. Free Radical Chain Reactions
in Organic Synthesis; Academic Press: London, 1991; (c)
Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions; VCH: Weinheim, 1996; (d) Linker, T.;
Schmittel, M. Radikaleund Radikalionen in der Organischen
Synthese; Wiley-VCH: Weinheim, 1998.
3. (a) Mandal, P. K.; Maiti, G.; Roy, S. C. J. Org. Chem.
1998, 63, 2829; (b) Roy, S. C.; Rana, K. K.; Guin, C. J.
Org. Chem. 2002, 67, 3242; (c) Banerjee, B.; Roy, S. C.
Synthesis 2005, 2913; (d) Banerjee, B.; Roy, S. C. Eur. J.
Org. Chem. 2006, 489.
In conclusion, we have developed a new methodology to
construct eight-membered ring ethers via radical cycliza-
tion of epoxides using titanocene(III) chloride as the
radical source. Further studies are in progress to extend
this protocol for the construction of higher-membered
heterocyclic rings and its application to the synthesis
of natural products and will be reported elsewhere.
4. Rajanbabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994,
116, 986, and references cited therein.
5. Justicia, J.; Oller-Lopez, J. L.; Campana, A. G.; Oltra, J. E.;
Cuerva, J. M.; Bunuel, E.; Cardenas, D. J. J. Am. Chem.
Soc. 2005, 127, 14911.
Acknowledgements
6. Typical experimental procedure for the radical cyclization
reaction: a solution of titanocene dichloride (498 mg,
2 mmol) in dry THF (25 mL) was stirred with activated
zinc dust (393 mg, 6 mmol) for 1 h under argon. The
resulting green solution was then transferred through a
cannula to a dropping funnel and was added dropwise to a
magnetically stirred solution of epoxy propargylic ether 3a
(188 mg, 1 mmol) in dry THF (35 mL) at room temperature
under argon over 8 h. The reaction mixture was stirred for
an additional 6 h and then decomposed with a saturated
aqueous solution of NaH2PO4. The volatiles were removed
under reduced pressure and the residue obtained was
extracted with diethyl ether (3 · 50 mL). The combined
ether layer was washed with brine (20 mL) and dried
(Na2SO4). Removal of the solvent under reduced pressure
afforded the product which was chromatographed over
silica gel (60–120 mesh) using 10% ethyl acetate in light
petroleum as eluent to yield 4a (52%) as a viscous oil along
with the reduced product 5a (12%) and another unidentified
product (18%). Spectral data of 4a: IR (neat): 3398, 2920,
S.K.M. thanks CSIR, New Delhi, for awarding the
fellowship.
References and notes
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2856, 1490, 1207, 1006, 777 cmÀ1 1H NMR (CDCl3,
;
300 MHz): d 2.58 (dd, J = 15.7, 10.9 Hz, 1H), 3.22 (dd,
J = 15.7, 4.9 Hz, 1H), 3.64–3.79 (m, 3H), 4.46 (dd, J = 15.5,
4.8 Hz, 1H), 4.94 (dd, J = 15.5, 2.4, Hz, 1H), 5.43–5.49 (m,
1H), 5.55–5.62 (m, 1H), 7.00–7.08 (m, 3H), 7.15–7.21 (m,
1H); 13C NMR (CDCl3, 75 MHz): d 35.6, 40.7, 67.2, 72.7,
122.7, 124.0, 126.7, 127.5, 130.7, 133.1, 133.4, 156.9. HRMS

S. K. Mandal, S. C. Roy / Tetrahedron Letters 47 (2006) 1599–1601
1601
calcd for [C12H14O2+Na]+ 213.0892, found 213.0880.
Spectral data of 7: IR (neat): 3398, 2922, 2873, 1488,
1218, 1008, 744 cmÀ1; 1H NMR (CDCl3, 300 MHz): d 1.43–
1.56 (m, 2H), 1.61–1.72 (m, 2H), 1.99–2.04 (m, 1H), 2.65–
2.72 (m, 1H), 2.83–2.88 (m, 1H), 3.41 (d, J = 6.3 Hz, 2H),
3.85 (t, J = 11.2 Hz, 1H), 4.24 (dd, J = 11.2, 4.3 Hz, 1H),
7.01–7.21 (m, 4H); 13C NMR (CDCl3, 75 MHz): d 30.2,
30.3, 30.8, 40.5, 65.0, 78.0, 121.2, 124.2, 127.5, 129.6, 136.7,
157.0. HRMS calcd for [C12H16O2+Na]+ 215.1047, found
215.1049.