Synthesis of tetrahydrofurans by cyclization of homoallylic alcohols with iodine/iodine(III)

Article abstract of DOI:10.1021/jo102413u

Tetrahydrofuran derivatives can be obtained by cyclofunctionalization of homoallylic alcohols bearing a terminal double bound by using [hydroxy(tosyloxy)iodo]benzene (HTIB, Kosers reagent) in the presence of a catalytic amount of I₂ (20 mol %)

Full text of DOI:10.1021/jo102413u

pubs.acs.org/joc
lized tetrahydrofurans are homoallylic alcohols, whose cy-
Synthesis of Tetrahydrofurans by Cyclization of
Homoallylic Alcohols with Iodine/Iodine(III)
clofunctionalization has been investigated by using different
electrophiles, such as halogens, iodine(III), thallium(III),
mercury(II), etc.1 However, the iodocyclization of homo-
allylic alcohols bearing a terminal double bond leads to four-
membered-ring derivatives or to complex mixtures,1,2
because the 5-endo-trig cyclization that would deliver
tetrahydrofuran derivatives is not favored according to
the Baldwin’s rules and the 4-exo-trig mode takes place.
Fragmentation reactions may also take place when 3-al-
kenols are treated with halogens.3
Ramon S. Vasconcelos,†,§ Luiz F. Silva Jr,*,§ and
Athanassios Giannis*,†
§
´
Departamento de Quımica Fundamental,
´
~
Instituto de Quımica, Universidade de Sao Paulo,
~
Caixa Postal 26077, CEP 05513-970 Sao Paulo SP, Brazil,
and Institut fu€r Organische Chemie, Fakultat fur Chemie
und Mineralogie, Universitat Leipzig, Johannisallee 29,
04103 Leipzig, Germany
†
€
€
€
Hypervalent iodine reagents constitute a class of reagents
that can be used for a number of oxidative transformations
with a high level of selectivity, constituting an alternative to
toxic heavy metals.4 Although the cyclization of unsaturated
carboxylic acids with I(III) has been described in several
papers,5 there are not many reports of the corresponding
reaction with unsaturated alcohols.6 Herein, we describe the
synthesis of diverse tetrahydrofurans from readily available
homoallylic alcohols bearing a terminal double bond using
I(III) in the presence of I2. This transformation represents a
formal 5-endo-trig cyclization, for which a mechanism is
proposed based on isolated intermediates.
luizfsjr@iq.usp.br; giannis@uni-leipzig.de
Received December 7, 2010
The preparation of the required homoallylic alcohols
1a-k was performed by reacting ketones with allyl magne-
sium bromide, except for substrate 1g, which was prepared
from 4-phenylcyclohexanone with Zn/allyl bromide. Con-
sidering our previous experience in the reaction of unsatu-
rated alcohols with HTIB,7 the first substrate studied was 1a,
which was treated with HTIB under different conditions.
The reaction of 1a with HTIB in MeOH or in MeCN led to
products of substitution (2) or elimination (3), respectively,
of the tertiary alcohol, without reaction at the double bond
(Scheme 1). These transformations presumably occur
through the formation of a benzylic carbocation, due to
Tetrahydrofuran derivatives can be obtained by cyclo-
functionalization of homoallylic alcohols bearing a term-
inal double bound by using [hydroxy(tosyloxy)iodo]-
benzene (HTIB, Koser’s reagent) in the presence of a
catalytic amount of I2 (20 mol %) in MeOH under mild
conditions. This transformation is an overall 5-endo-trig
cyclization, which occurs by two different pathways. The
first is a 4-exo-trig cyclization followed by ring expansion,
whereas the second is an electrophilic addition followed
by a 5-endo-tet cyclization.
(3) Examples: (a) Yadav, J. S.; Chawls, H. P. S.; Dev, S. Tetrahedron Lett.
1977, 201. (b) Yadav, J. S.; Patil, D. G.; Krishna, R. R.; Chawla, H. P. S.;
Dev, S. Tetrahedron 1982, 38, 1003. (c) Silva, L. F., Jr.; Quintiliano, S. A. P.
Tetrahedron Lett. 2009, 50, 2256.
(4) Selected recent reviews: (a) Varvoglis, A. Hypervalent Iodine in
Organic Synthesis; Academic Press: London, UK, 1997. (b) Koser, G. F.
Aldrichim. Acta 2000, 34, 89. (c) Hypervalent Iodine Chemistry; Wirth, T.,
Ed.; Springer: Berlin, Germany, 2003. (d) Moriarty, R. M. J. Org. Chem.
2005, 70, 2893. (e) Silva, L. F., Jr. Molecules 2006, 11, 421. (f) Ciufolini,
M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai, D. Synthesis
2007, 24, 3759. (g) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(h) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052.
The tetrahydrofuran moiety is present in several molecules
with biological activity, including important natural
products.1 Thus, a plethora of different methods have been
developed to obtain this structural motif.1 One of them is the
cyclofunctionalization of unsaturated alcohols mediated by
electrophiles.1 Appropriate substrates to obtain functiona-
ꢁ
(i) Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 2235.
(1) Reviews: (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309. (b) Cardillo,
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Tetrahedron 1993, 4, 1711. (d) French, A. N.; Bissmire, S.; Wirth, T. Chem.
Soc. Rev. 2004, 33, 354. (e) da Silva, F. M.; Jones, J.; de Mattos, M. C. S.
Curr. Org. Synth. 2005, 2, 393. (f) Togo, H.; Iida, S. Synlett 2006, 2159.
(g) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261. (h) Jalce, G.; Franck,
(5) Examples: (a) Shah, M.; Taschner, M. J.; Koser, G. F.; Rach, N. L.;
Jenkins, T. E.; Cyr, P.; Powers, D. Tetrahedron Lett. 1986, 27, 5437. (b) Shah,
M.; Taschner, M. J.; Koser, G. F.; Rach, N. L. Tetrahedron Lett. 1986, 27,
4557. (c) Koser, G. F.; Lodaya, J. S.; Ray, D. G.; Kokil, P. B. J. Am. Chem.
Soc. 1988, 110, 2987. (d) Boye, A. C.; Meyer, D.; Ingison, C. K.; French,
A. N.; Wirth, T. Org. Lett. 2003, 5, 2157. (e) Liu, H.; Tan, C.-H. Tetrahedron
Lett. 2007, 48, 8220. (f) Yan, J.; Wang, H.; Yang, Z.; He, Y. Synlett 2009,
2669. (g) Uyanik, M.; Yasui, T.; Ishihara, K. Bioorg. Med. Chem. Lett. 2009,
19, 3848. (h) Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2010,
49, 2175. (i) Uyanik, M.; Yasui, T.; Ishihara, K. Tetrahedron 2010, 66, 5841.
(6) Examples: (a) Kim, H.-j.; Schlecht, M. F. Tetrahedron Lett. 1987, 28,
5229. (b) Sawaguchi, M.; Hara, S.; Fukuhara, T.; Yoneda, N. J. Fluorine
Chem. 2000, 104, 277. (c) Giannis, A.; Heretsch, P.; Sarli, V.; Stossel, A.
Angew. Chem., Int. Ed. 2009, 48, 7911. (d) Uyanik, M.; Okamoto, H.; Yasui,
T.; Ishihara, K. Science 2010, 328, 1376.
G.; Orena, M. Tetrahedron 1990, 46, 3321. (c) Harmange, J.-C.; Figadere, B.
ꢁ
X.; Figadere, B. Tetrahedron: Asymmetry 2009, 20, 2537. (i) Silva, L. F., Jr.;
Carneiro, V. M. T. Synthesis 2010, 1059.
(2) Examples: (a) Evans, R. D.; Magee, J. W.; Schauble, J. H. Synthesis
1988, 862. (b) Galatsis, P.; Parks, D. J. Tetrahedron Lett. 1994, 35, 6611.
(c) Galatsis, P.; Millan, S. D.; Ferguson, G. J. Org. Chem. 1997, 62, 5048. (d)
Wang, G.; Wang, Y.; Arcari, J. T.; Howell, A. R.; Rheingold, A. L.;
Concolino, T. Tetrahedron Lett. 1999, 40, 7051. (e) Bedford, S. B.; Bell,
K. E.; Bennett, F.; Hayes, C. J.; Knight, D. W.; Shaw, D. E. J. Chem. Soc.,
Perkin Trans. 1 1999, 2143. (f) Rofoo, M.; Roux, M.-C.; Rousseau, G.
Tetrahedron Lett. 2001, 42, 2481. (g) Robin, S.; Rousseau, G. Eur. J. Org.
Chem. 2002, 3099.
(7) Silva, L. F., Jr.; Vasconcelos, R. S.; Nogueira, M. A. Org. Lett. 2008,
10, 1017.
DOI: 10.1021/jo102413u
r
Published on Web 01/18/2011
J. Org. Chem. 2011, 76, 1499–1502 1499
2011 American Chemical Society

Vasconcelos et al.
JOCNote
SCHEME 1. Reaction of 1a with HTIB
were isolated. In striking contrast, treatment of 1b with I2
under classical cyclization conditions gave only the oxetane
5b (Scheme 2). We proposed a mechanism for the formal
5-endo-trig cyclization of 1b, which relays mainly on oxida-
tive displacement of iodine from alkyl iodides11 and the ring
expansion of cyclic ethers having an iodoalkyl sub-
stituent12,13 that were both described with use of I(III). These
reactions are possible due to the oxidation of an alkyl iodide
to the corresponding I(III) species, which is a hypernucleo-
fuge.14 Thus, first I2 would attack the double bond of alcohol
1b. Iodonium ion 7 has two pathways to follow. In route a,
the formation of the oxetane 5b would take place by a 4-exo-
trig process in 7. Then, oxetane 5b would be oxidized to the
unstable alkyl I(III) species 8, which is prone to formation of
the bicyclic oxonium ion 10, by the displacement of the
hypervalent iodine group by oxygen. MeOH would add to
oxonium 10 producing 4b,15 after deprotonation. In route b,
the methoxy alkyl iodide 6 would be formed by addition of
MeOH to the iodonium ion 7. Oxidation of the iodide group
of 6 could convert it into a hypernucleofuge (11). The
intramolecular attack of the hydroxy group to the I(III)
moiety of 12 would displace the iodine group leading to 13,
through a 5-exo-tet process (Scheme 3).
SCHEME 2. Cyclization Reactions of 1b
SCHEME 3. Mechanisms for the Cyclization of 1b with I2/DIB
The reaction scope was then investigated. As shown in
Table 1 (entries 1-9), substituted tetrahydrofurans bearing a
spiro cyclic unit were obtained in moderate to good yield. On
the other hand, the substrate 1k gave only the oxetane 5k
(entry 10). Moreover, the unsaturated alcohol 1a led to a
complex mixture under similar conditions. During the opti-
mization process, we found that higher yields of the desired
product are obtained with HTIB instead of DIB. Addition-
ally, this modification decreased reaction times and the
amount of hypervalent iodine and I2 (cf. entries 1, 4, and
7). The alcohol moiety of the substrate can be either in cyclic
(cf. entries 1-3, 5-8) or in acyclic (cf. entries 4 and 9)
systems. The diastereoselectivity observed in the cyclization
of 1h-j (entries 7-9) is low to moderate. However, this
selectivity is higher than that observed in similar reactions.16
The transformation of homoallylic alcohols into spirocyclic
ethers analogous to 4 has been reported by using, for
example, Pd(II)/DIB;16 NaIO4:NaHSO3;17 epoxidation fol-
lowed acid hydrolysis/cyclization;18 and bromine addition
followed by treatment with base.19 Compared to these pre-
vious works, the present methodology has the advantage to
be one step, metal-free, and of simple operation. As MeOH is
incorporated in the final product, we expected that different
tetrahydrofuran derivatives would be obtained changing the
the acidic medium. When 1a was exposed to HTIB in the
presence of base (1 equiv of HTIB, 2.4 equiv of NaHCO3,
MeOH, rt), no reaction was observed even after 4 days. An
analogous result was observed by treating 1a with diacetox-
yiodobenzene (DIB) under several conditions.8
After these disappointing initial results and inspired by
previous works,9,10 we decided to investigate the reaction of
homoallylic alcohols with the combination I(III)/I2. For
these tests, the substrate 1b was selected, which would be
less prone to carbocation formation than 1a. Gratefully, the
reaction of 1b with DIB and I2 gave the tetrahydrofuran 4b in
60% yield. The course of this cyclization was monitored by
TLC analysis. Initially, alkenol 1b originated two different
compounds (oxetane 5b and iodide 6), which led to the
desired cyclic ether 4b as time progressed. Interrupting the
reaction in the beginning, the reaction intermediates 5b and 6
(11) Gallos, J.; Varvoglis, A. J. Chem. Soc., Perkin Trans. 1 1983, 1999.
(12) Abo, T.; Sawaguchi, M.; Senboku, H.; Hara, S. Molecules 2005, 10,
183.
(13) Inagaki, T.; Nakamura, Y.; Sawaguchi, M.; Yoneda, N.; Ayuba, S.;
Hara, S. Tetrahedron Lett. 2003, 44, 4117.
(14) It was estimated that the I(III) is a better leaving group than I by a
factor of 1013-14. For a discussion, see: Ochiai, M. Reactivities, Properties
and Structures, in Hypervalent Iodine Chemistry: Modern Developments in
Organic Synthesis. Top. Curr. Chem. 2003, 5–68.
(15) Ferraz, H. M. C.; Ribeiro, C. M. R.; Grazini, M. V. A.; Brocksom,
T. J.; Brocksom, U. Tetrahedron Lett. 1994, 35, 1497.
(16) Li, Y.; Song, D.; Dong, V. M. J. Am. Chem. Soc. 2008, 130, 2962.
(17) Okimoto, Y.; Kikuchi, D.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett.
2000, 41, 10223.
(8) Conditions tested were the following: (a) 1 equiv of DIB, MeOH, rt,
30 min; (b) 1 equiv of DIB, MeCN, rt (3 d), reflux (7 h); (c) 1 equiv of DIB,
3.0 equiv of KOH, MeOH, rt, 4 d.
(18) Chirskaya, M. V.; Vasil’ev, A. A.; Shorshnev, S. V.; Sviridov, S. I.
Russ. Chem. Bull. 2006, 55, 1300.
(9) Djuardi, E.; Mc Nelis, E. Tetrahedron Lett. 1999, 40, 7193.
(10) Herault, X.; McNelis, E. Tetrahedron 1996, 52, 10267.
(19) Chirskaya, M. V.; Vasil’ev, A. A.; Sergovskaya, N. L.; Shorshnev,
S. V.; Sviridov, S. I. Tetrahedron Lett. 2004, 45, 8811.
1500 J. Org. Chem. Vol. 76, No. 5, 2011

Vasconcelos et al.
JOCNote
TABLE 1. Reaction of 1b-k with I2/DIB (A and B) or with I2/HTIB (C)b
In summary, a new protocol to obtain tetrahydrofuran
derivatives by treatment of readily available homoallylic
alcohols with I(III) in the presence of I2 under mild condi-
tions was developed. This simple, one-step, and metal-free
procedure has great applicability in the synthesis of biologi-
cally active natural products. Reaction intermediates were
isolated and characterized giving support for two mechan-
isms. One of them would be a 4-exo-trig cyclization followed
by ring expansion, whereas the second would be an electro-
philic addition followed by 5-endo-tet cyclization.
Experimental Section
3-Methoxy-1-oxa-spiro[4,5]decano (4b). To a stirred solution
of 1b (0.035 g, 0.25 mmol) and I2 (0.013 g, 0.050 mmol) in MeOH
(1 mL) at 0 °C was slowly added HTIB (0.196 g, 0.500 mmol).
The mixture was stirred for 16 h at rt. The reaction was
quenched with a 10% solution of Na2SO3 (6 mL) and extracted
with EtOAc (4 ꢀ 4 mL). The organic phase was washed with a
saturated solution of NaHCO3 (4 mL) and brine (4 mL), then
dried over anhydrous MgSO4. The solvent was removed under
reduced pressure. The crude product was purified by column
(10-20% Et2O in pentane), giving 4b (0.027 g, 64%) as a
1
colorless oil. IR (film): 2931, 2857, 1448, 1102, 1088, 1071. H
NMR (300 MHz, CDCl3): δ 1.36-1.68 (m, 10H), 1.79 (ddd, J =
0.6, 3.6, 13.4 Hz, 1H), 1.85 (dd, J = 6.0, 13.4 Hz, 1H), 3.27 (s,
3H), 3.83 (ddd, J = 0.6, 3.3, 9.8 Hz, 1H), 3.89 (dd, J = 4.7, 9.8
Hz, 1H), 3.97 (dddd, J = 3.3, 3.6, 4.7, 6.0 Hz, 1H). 13C NMR (75
MHz, CDCl3): δ 23.6, 23.7, 25.5, 37.27, 37.33, 42.5, 56.8, 70.5,
81.9, 82.5. LRMS m/z (%): 170 (M•þ, 23), 139 (44), 127 (96), 114
(30), 95 (100). HRMS [ESI(þ)] calcd for [C10H18O2þNa]þ
193.11990, found 193.12012.
3-Methoxy-1-oxa-spiro[4,6]undecane (4c). As for 4b, but with
1c (0.039 g, 0.25 mmol), I2 (0.013 g, 0.050 mmol), MeOH (1 mL),
HTIB (0.196 g, 0.500 mmol), and 15 h. Purification (10% Et2O
in pentane) gave 4c (0.020 g, 44%) as a colorless oil. IR (film):
1058, 1078, 1102, 1460, 2857, 2927 cm-1. 1H NMR (300 MHz,
CDCl3): δ 1.30-1.44 (m, 2H), 1.46-1.68 (m, 6H), 1.70-1.92 (m,
6H), 3.28 (s, 3H), 3.81 (ddd, J = 0.6, 3.3, 9.8 Hz, 1H), 3.89 (dd,
J = 5.0, 9.8 Hz, 1H), 3.95-4.01 (m, 1H). 13C NMR (75 MHz,
CDCl3): δ 22.7, 29.11, 29.13, 40.3, 40.6, 44.2, 56.8, 70.6, 81.9,
86.2. LRMS m/z (%) 184 (M•þ, 35), 153 (48), 141 (73), 127 (100),
109 (25), 95 (89). HRMS [ESI(þ)] calcd for [C11H20O2 þ H]þ
185.1536, found 185.1535.
3-Methoxy-1-oxa-spiro[4,11]hexadecane (4d). As for 4b, but
with 1d (0.056 g, 0.25 mmol), I2 (0.013 g, 0.050 mmol), MeOH (1
mL), HTIB (0.196 g, 0.500 mmol), and 22 h. Purification (10%
EtOAc in hexane) gave 4d (0.035 g, 55%) as a colorless oil. IR
(film): 733, 1074, 1099, 1445, 1471, 2243, 2863, 2934 cm-1. 1H
NMR (300 MHz, CDCl3): δ 1.34 (s, 19H), 1.46-1.63 (m, 2H),
1.71-1.76 (m, 1H), 1.76 (dd, J = 3.3, 13.3 Hz, 1H), 1.84 (dd, J =
6.7, 13.3 Hz, 1H), 3.27 (s, 3H), 3.79 (dd, J = 3.2, 9.8 Hz, 1H),
3.91 (dd, J = 5.3, 9.8 Hz, 1H), 4.00 (dddd, J = 3.2, 3.3, 5.3, 6.7
Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 19.9, 22.1, 22.2, 22.45,
22.46, 26.0, 26.43, 26.44, 32.9, 33.3, 42.5, 56.8, 70.7, 82.1, 85.8.
LRMS m/z (%): 254 (M•þ, 44), 223 (90), 183 (48), 127 (100), 95
(90). HRMS [ESI(þ)] calcd for [C16H30O2 þ Na]þ 277.21435,
found 277.21380.
2,2-Dibutyltetrahydro-4-methoxyfuran (4e). As for 4b, but
with 1e (0.046 g, 0.25 mmol), I2 (0.013 g, 0.050 mmol), MeOH
(1 mL), HTIB (0.196 g, 0.500 mmol), and 16 h. Purification
(10% EtOAc in hexane) gave 4e (0025 g, 47%) as a colorless oil.
IR (film): 1079, 1101, 1195, 1241, 1378, 1466, 1742, 2872, 2932
cm-1. 1H NMR (300 MHz, CDCl3): δ 0.89 (t, J = 7.0 Hz, 6H),
1.19-1.35 (m, 8H), 1.38-1.67 (m, 4H), 1.76 (dd, J = 3.5, 13.3
a3 equiv of HTIB. bA: 4 equiv of DIB, 0.5 equiv of I2, MeOH, rt. B: 4
equiv of DIB, 0.2 equiv of I2, MeOH, 60-70 °C. C: 2 equiv of HTIB, 0.2
equiv of I2, MeOH, rt. D: 2 equiv of HTIB, 20 mol % of I2, CH3CN/H2O
4:1, rt, 4 days.
solvent. Indeed, when the reaction was performed in water,
the desired hydroxy tetrahydrofuran 14 was obtained. How-
ever, the best yield was only 33% yield (entry 11).20
(20) See the Supporting Information for additional conditions.
J. Org. Chem. Vol. 76, No. 5, 2011 1501

Vasconcelos et al.
JOCNote
Hz, 1H), 1.89 (dd, J = 6.9, 13.3 Hz, 1H), 3.28 (s, 3H), 3.78 (dd,
J = 3.5, 9.6 Hz, 1H), 3.90 (dd, J = 5.2, 9.6 Hz, 1H), 3.98 (dddd,
J = 3.5, 3.5, 5.2, 6.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
14.1, 23.3, 26.4, 26.6, 37.9, 38.1, 41.4, 56.9, 70.9, 81.9, 85.3.
LRMS m/z (%): 157 (100), 125 (80). HRMS [ESI(þ)] calcd for
[C13H26O2 þ Na]þ 237.18305, found 237.18250.
3H). 13C NMR (MHz, CDCl3): δ major 22.1, 25.6, 26.3, 26.9,
33.9, 34.8, 38.3, 39.1, 40.9, 50.2, 57.0, 71.9, 81.4, 83.8; δ minor
22.0, 25.4, 26.4, 26.9, 34.0, 35.0, 38.0, 38.6, 40.8, 49.4, 56.7, 71.1,
81.4, 83.9. LRMS m/z (%): 224 (M•þ, 8), 181 (50), 127 (41), 114
(22), 95 (52), 79 (41). HRMS [ESI(þ)] calcd for [C14H24O2 þ H]þ
225.1849, found 225.1848.
Dihydro-4-methoxyspiro[furan-2(3H),20-tricyclo[3.3.1.13.7]-
decane] (4f). As for 4b, but with 1f (0.048 g, 0.25 mmol), I2 (0.013
g, 0.050 mmol), HTIB (0.294 g, 0.750 mmol), MeOH (1 mL), and
41 h. Purification (10-20% EtOAc in hexane) gave 4f (0.011 g,
20%) as a colorless oil. IR (film): 1099, 1108, 1452, 2853, 2905
(()-4-Methoxy-2-methyl-2-phenyltetrahydrofuran (4j). As for
4b, but with 1j (0.162 g, 1.00 mmol), I2 (0.051 g, 0.20 mmol),
HTIB (1.18 g, 3.00 mmol), MeOH (4 mL), and 4 days. Purifica-
tion (5-10% THF in hexane) gave 4j (0.048 g, 25% and 0.035 g,
18%) as two diastereomers. Major: IR (film): 703, 765, 1032,
1094, 1122, 1446, 1492, 2825, 2886, 2932, 2977, 3026, 3060, 3082.
1H NMR (300 MHz, CDCl3): δ 1.59 (s, 3H), 2.16-2.21 (m, 1H),
2.46 (dd, J = 6.5, 13.2 Hz, 1H), 3.31 (s, 3H), 3.88-3.98 (m, 2H),
4.01-4.04 (m, 1H), 7.18-7.25 (m, 1H), 7.29-7.34 (m, 2H),
7.37-7.40 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 30.5, 45.4,
56.8, 71.6, 82.0, 84.3, 124.5, 126.5, 128.2, 147.8. LRMS m/z (%):
177 (100), 145 (38), 115 (20), 105 (48), 91 (20). HRMS [ESI(þ)]
calcd for [C12H16O2 þ H]þ 193.1229, found 193.1225. Minor: IR
(film): 701, 763, 1082, 1113, 1447, 1492, 2828, 2856, 2926, 2961,
3026, 3060, 3088. 1H (300 MHz, CDCl3): δ 1.50 (s, 3H),
2.23-2.38 (m, 2H), 3.18 (s, 3H), 3.84-3.90 (m, 1H),
4.10-4.18 (m, 2H), 7.18-7.25 (m, 1H), 7.29-7.34 (m, 2H),
7.39-7.43 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 30.1, 45.2,
56.7, 71.7, 81.8, 84.1, 124.6, 126.3, 128.1, 147.6. LRMS m/z (%):
177 (100), 145 (58), 115 (35), 105 (77), 91 (41). HRMS [ESI(þ)]
calcd for [C12H16O2 þ Na]þ 215.1048, found 215.1046.
cm-1 1H NMR (200 MHz, CDCl3): δ 1.49-1.97 (m, 14H),
.
2.10-2.25 (m, 2H), 3.29 (s, 3H), 3.87-4.00 (m, 3H). 13C NMR
(50 MHz, CDCl3): δ 26.8, 27.2, 27.8, 33.2, 33.6, 35.4, 35.9, 36.8,
37.1, 37.7, 41.4, 56.8, 70.1, 82.0, 86.4. LRMS m/z (%): 222 (M•þ
,
17), 192 (14), 175 (8), 160 (23), 91 (46), 79 (57), 41 (100). HRMS
[ESI(þ)] calc for [C14H23O2 þ H]þ 223.1693, found 223.1690.
3-Methoxy-8-phenyl-1-oxaspiro[4,5]decane (4g). As for 4b,
but with 1g (0.061 g, 0.282 mmol), HTIB (0.221 g, 0.563 mmol),
I2 (0.014 g, 0.056 mmol), MeOH (1.0 mL), and 20 h. Purification
(20% Et2O in hexane) gave 4g (0.042 g, 60%) as a colorless oil.
IR (film): 533, 700, 756, 1046, 1072, 1095, 1108, 1441, 1493,
2858, 2927, 3027, 3060, 3083 cm-1 1H NMR (300 MHz,
.
CDCl3): δ 1.45-1.57 (m, 2H), 1.68-1.94 (m, 7H), 2.08 (ddd,
J = 3.0, 5.9, 13.6 Hz, 1H), 2.48 (tt, J = 3.5, 12.1 Hz, 1H), 3.30 (s,
3H), 3.86-3.96 (m, 2H), 3.98-4.04 (m, 1H), 7.14-7.19 (m, 1H),
7.22-7.30 (m, 4H). 13C NMR (50 MHz, CDCl3): δ 30.2, 30.4,
36.8, 37.1, 43.7, 44.5, 56.8, 70.9, 80.8, 81.7, 125.8, 126.9, 128.2,
147.3. LRMS m/z (%): 246 (M•þ, 2), 127 (100), 104 (17), 91 (22),
77 (10). HRMS [ESI(þ)] calcd for [C16H22O2 þ Na]þ 269.1512,
found 269.1510.
(2S,40R or 40S)-40-(Iodomethyl)-1,7,7-trimethylspiro[bicyclo-
[2.2.1]heptane-2,20-oxetane] (5k). As for 4b, but with (þ)-1k
(0.049 g, 0.25 mmol), I2 (0.013 g, 0.050 mmol), HTIB (0.196 g,
0.500 mmol), MeOH (1.0 mL), and 16 h. Purification (5%
EtOAc in hexanes) gave 5k (0.026 g, 33%) as a colorless oil
and a 3:2 mixture of diastereomers. IR (film): 786, 1008, 1387,
(3-RS)-(4,5R,6S,9R)-6-Isopropyl-3-methoxy-9-methyl-1-oxa-
spiro[4,5]-decane (4h). As for 4b, but with (þ)-1h (0.049 g, 0.25
mmol), I2 (0.013 g, 0.050 mmol), HTIB (0.294 g, 0.750 mmol),
MeOH (1 mL), and 26 h. Purification (0-5% Et2O in CH2Cl2)
gave 4h (0.032 g, 57%) as a colorless oil and as a 1:1 mixture of
diastereomers. IR (KBr): 1063, 1090, 1114, 1139, 1365, 1456,
2867, 2927, 2951 cm-1. 1H NMR (300 MHz, CDCl3): δ major
0.81-0.93 (m, 11H), 1.02-1.12 (m, 1H), 1.38-1.58 (m, 3H),
1.61-1.77 (m, 3H), 1.85-1.99 (m, 1H), 2.06-2.31 (m, 1H), 3.31
(s, 3H), 3.66-4.03 (m, 3H); δ minor 0.81-0.93 (m, 11H),
1.02-1.12 (m, 1H), 1.38-1.58 (m, 3H), 1.61-1.77 (m, 3H),
1.85-1.99 (m, 1H), 2.06-2.31 (m, 1H), 3.28 (s, 3H), 3.66-4.03
(m, 3H). 13C NMR (75 MHz, CDCl3): δ major 18.1, 21.8, 22.3,
23.9, 26.4, 28.8, 35.0, 41.6, 48.5, 49.2, 57.2, 71.0, 81.3, 85.8; δ
minor 18.1, 22.1, 22.3, 23.9, 25.9, 28.7, 35.1, 41.5, 47.6, 48.6,
56.6, 70.4, 81.4, 86.0. LRMS m/z (%): major 226 (M•þ, 7), 211
(5), 195 (5), 183 (4), 169 (10), 155 (11), 141 (100), 123 (7), 109
(47), 95 (8); minor 226 (M•þ, 7), 211 (6), 195 (5), 183 (3), 169 (12),
155 (15), 141 (100), 123 (8), 109 (46), 95 (8). HRMS [ESI(þ)]
calcd for [C14H26O2 þ Na]þ 249.18305, found 249.18250.
(()-4-Methoxydecahydro-20H,3H-spiro[furan-2,10-naphthalene]
(4i). As for 4b, but with 1i (0.049 g, 0.250 mmol), I2 (0.013 g,
0.050 mmol), HTIB (0.294 g, 0.750 mmol), MeOH (1 mL), and
45 h. Purification (10-20% Et2O in hexane) gave 4i (0.028 g,
50%) as a colorless oil and as a 2:1 mixture of diastereomers. IR
(film): 1066, 1097, 1122, 1447, 2850, 2927 cm-1. 1H NMR (200
MHz, CDCl3): δ major 0.89-0.97 (m, 4H), 1.17-1.25 (m, 6H),
1.51-1.81 (m, 6H), 1.89-2.25 (m, 2H), 3.30 (s, 3H), 3.74-3.95
(m, 3H); δ minor 0.89-0.97 (m, 4H), 1.17-1.25 (m, 6H), 1.51-
1.81 (m, 6H), 1.89-2.25 (m, 2H), 3.28 (s, 3H), 3.74-3.95 (m,
1427, 1454, 2933, 2962, 2993 cm-1 1H NMR (400 MHz,
.
CDCl3): δ major 0.94 (s, 3H), 1.00 (s, 3H), 1.05 (s, 4H),
1.27-1.33 (m, 1H), 1.36-1.50 (m, 2H), 1.59-1.62 (m, 1H),
1.70-1.71 (m, 1H), 1.76 (dd, J = 3.7, 13.3 Hz, 1H), 1.94 (ddd,
J = 2.6, 4.2, 9.6 Hz, 1H), 2.09 (dd, J = 9.2, 13.3 Hz, 1H), 3.19
(dd, J = 8.5, 9.4 Hz, 1H), 3.33 (dd, J = 5.0, 9.4 Hz, 1H),
4,21-4,31 (m, 1H); δ minor 0.93 (s, 3H), 1.00 (s, 3H), 1.03 and
1.05 (s, 4H), 1.27-1.33 (m, 1H), 1.36-1.50 (m, 2H), 1.59-1.62
(m, 2H), 1.68-1.69 (m, 1H), 2.04 (ddd, J = 1.7, 2.6, 9.6 Hz, 1H),
2.19 (dd, J = 6.0, 12.6 Hz, 1H), 3.01 (dd, J = 9.4, 9.4 Hz, 1H),
3.37 (dd, J = 4.3, 9.4 Hz, 1H), 4.21-4.31 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ major 11.3, 16.3, 22.9, 23.5, 24.7, 26.4,
34.6, 39.0, 44.9, 50.3, 58.7, 78.3, 93.4; δ minor 11.9, 21.0, 23.0,
23.5, 24.7, 25.9, 36.6, 40.9, 46.3, 49.2, 60.0, 79.0, 92.6. HRMS
[ESI(þ)] calcd for [C13H21IO þ H]þ 321.07098, found 321.07127.
Acknowledgment. The authors wish to thank FAPESP,
CNPq, and CAPES for financial support, and Dr. L. Hennig
for discussion.
Supporting Information Available: Spectroscopic data and
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
Note Added after ASAP Publication. There was an error in
reference 14 in the version published on 1/18/2011. This was
fixed in the version published on 1/31/2011.
1502 J. Org. Chem. Vol. 76, No. 5, 2011