Stereospecific consecutive epoxide ring expansion with dimethylsulfoxonium methylide

Article abstract of DOI:10.1021/jo101330p

Figure presented. Consecutive ring-expansion reactions of oxiranes with dimethylsulfxonium methylide were studied experimentally and modeled computationally at the density functional theory (DFT) and second-order Moller-Plesset (MP2) levels of theory utilizing a polarizable continuum model (PCM) to account for solvent effects. While the epoxide to oxetane ring expansion requires 13-17 kcal mol^-1 activation and occurs at elevated temperatures, the barriers for the ring expansions to oxolanes are higher (ca. 25 kcal mol^-1) and require heating to 125 °C. Further expansions of these oxolanes to the six-membered oxanes are hampered by high barriers (ca. 40 kcal mol^-1). We observe the complete conservation of the enantiomeric purities for the nucleophilic ring expansions of enantiomeric 2-mono- and 2,2-disubstituted epoxides and oxetanes with dimethylsulfoxonium methylide. This is a convenient general approach for the high-yielding preparation of optically active four- and five-membered cyclic ethers from oxiranes.

Full text of DOI:10.1021/jo101330p

pubs.acs.org/joc
Stereospecific Consecutive Epoxide Ring Expansion with
Dimethylsulfoxonium Methylide
Ekaterina D. Butova,§,‡ Anastasiya V. Barabash,§ Anna A. Petrova,§ Christian M. Kleiner,‡
Peter R. Schreiner,*,‡ and Andrey A. Fokin*,§,‡
§Department of Organic Chemistry, Kiev Polytechnic Institute, pr. Pobedy 37, 03056 Kiev, Ukraine, and
‡Institut fu€r Organische Chemie, Justus-Liebig University, Heinrich-Buff-Ring 58,
D-35392 Giessen, Germany
prs@org.chemie.uni-giessen.de; aaf@xtf.ntu-kpi.kiev.ua
Received July 6, 2010
Consecutive ring-expansion reactions of oxiranes with dimethylsulfxonium methylide were studied
experimentally and modeled computationally at the density functional theory (DFT) and second-
order Møller-Plesset (MP2) levels of theory utilizing a polarizable continuum model (PCM) to
account for solvent effects. While the epoxide to oxetane ring expansion requires 13-17 kcal mol-1
activation and occurs at elevated temperatures, the barriers for the ring expansions to oxolanes
are higher (ca. 25 kcal mol-1) and require heating to 125 °C. Further expansions of these oxolanes to
the six-membered oxanes are hampered by high barriers (ca. 40 kcal mol-1). We observe the complete
conservation of the enantiomeric purities for the nucleophilic ring expansions of enantiomeric
2-mono- and 2,2-disubstituted epoxides and oxetanes with dimethylsulfoxonium methylide. This is
a convenient general approach for the high-yielding preparation of optically active four- and five-
membered cyclic ethers from oxiranes.
Introduction
liability, and basicity of the nearby amine group.7 Optically
active oxetanes are important intermediates in the preparation
of biologically active compounds, such as sarracenin,8 ero-
gorgiaene,9,10 and some others.11 Chiral oxetanes are also
intermediates in organic synthesis: the enantioselective oxetane
ring openings promoted by Lewis acids12 or peroxides13 give,
respectively, hydroxyketones and 3-hydroperoxyalkanols,
whereas with Brønsted acids optically active alkenes, unsaturated
Small four- and five-membered cyclic ethers (oxetanes and
oxolanes) are the key structural fragments of many biologi-
cally active compounds. For instance, the oxetane ring is
present in taxol1,2 and its analogue baccatin,3 laureatin,4
oxetin,5 and oxetanocin.6 The incorporation of an oxetane
ring into the structure of N,N-dimethyl-4-(p-tert-butylphenyl)-
butylamine results in remarkable changes of its physicochem-
ical characteristics such as lipophilicity, amphiphilicity, hERG
€
(7) Wuitschik, G.; Rogers-Evans, M.; Muller, K.; Fischer, H.; Wagner,
B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew. Chem., Int. Ed. 2006,
45, 7736–7739.
(1) Samaranayake, G.; Magri, N. F.; Jitrangsri, C.; Kingston, D. G. J.
Org. Chem. 1991, 56, 5114–5119.
(2) Heiberg, H.; Johansson, L.; Gropen, O.; Ryan, O. B.; Swang, O.;
Tilset, M. J. Am. Chem. Soc. 2000, 122, 10831–10845.
(3) Samaranayake, G.; Neidigh, K. A.; Kingston, D. G. J. Nat. Prod.
1993, 56, 884–898.
(4) Sugimoto, M.; Suzuki, T.; Hagiwara, H.; Hoshi, T. Tetrahedron Lett.
2007, 48, 1109–1112.
(5) Omura, S.; Murata, M.; Imamura, N.; Iwai, Y.; Tanaka, H.; Furusaki,
A.; Matsumoto, T. J. Antibiot. 1984, 37, 1324–1332.
(8) Hoye, T. R.; Richardson, W. S. J. Org. Chem. 1989, 54, 688–693.
(9) Harmata, M.; Hong, X.; Schreiner, P. R. J. Org. Chem. 2008, 73,
1290–1296.
(10) Yadav, J. S.; Basak, A. K.; Srihari, P. Tetrahedron Lett. 2007, 48,
2841–2843.
(11) Trost, B. M.; Chisholm, J. D.; Wrobleski, S. T.; Jung, M. J. Am.
Chem. Soc. 2002, 124, 12420–12421.
(12) Bach, T.; Eilers, F. J. Org. Chem. 1999, 64, 8041–8044.
(13) Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4,
4591–4593.
(6) Saksena, A. K.; Ganguly, A. K.; Girijavallabhan, V. M.; Pike, R. E.;
Chen, Y.-T.; Puar, M. S. Tetrahedron Lett. 1992, 33, 7721–7724.
(14) Marchand, A. P.; Wang, Y.; Ren, C.-t.; Vidyasagar, V.; Wang, D.
Tetrahedron 1996, 52, 6063–6072.
DOI: 10.1021/jo101330p
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2010 American Chemical Society

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SCHEME 1. Consecutive Oxacycle Ring Expansion with Dimethylsulfoxonium Methylide (1)
alcohols, or diols form.14,15 The stereoselective reductive
opening of oxetanes with lithium powder in the presence of
catalytic amounts of DTBB followed by treatment with
various electrophiles leads to optically active alcohols.16
The oxolane ring is a fragment of many enantiomerically
pure marine polycyclic esters,17 alkaloids,18-22 lignanes,23
and terpenoids.24
The existing procedures for the preparation of optically
active oxetanes and oxolanes utilizing diols,13,14 oxiranes,11
ketones,25 acetaldehyde and cyclopentadiene,8 tosylates,10
etc.26 either require many steps14,27 or expensive reagents or
give products with low enantiomeric excess.25 It is well
documented that the methylenation of epoxides with di-
methylsulfoxonium methylide (1) produces oxetanes in good
yields under mild reaction conditions.28
epoxidations or through a large variety of other methods.39-49
Only recently optically active 2-(3-chlorophenyl)oxetane was
obtained via ring expansion of 3-chlorostyreneoxide.50 For the
preparation of optically active 2,2-disubstituted oxetanes the
one-pot consecutive methylenation of prochiral ketones in the
presence of an optically active heterobimetallic complex was
suggested.51 The reaction involves the formation52 of optically
active oxiranes; the enantiopurity was slightly amplified in the
second step as a result of partial kinetic resolution of the
intermediates. This transformation is applicable to the prepara-
tion of optically pure (ee > 99%) methyl oxetanes in good
preparative yields (62-88%). However, the results are quite
sensitive to the substitution pattern. While phenylethylketone
displays an enantioselectivity of 91%, the chemical yield was
only 26%. Thus, the extension of this approach to the enantio-
selective preparation of a larger variety of 2,2-substituted oxi-
ranes may be problematic, mostly because of ee loss in the first
Therefore it is somewhat surprising that the methylena-
tion of optically active epoxides with 1 has not received
more attention, since they are readily available in high ee
via Sharpless29,30 or Shi14,31-34 as well as many other35-38
step and insufficient enantioamplification in the second.51
A
more general approach to optically active oxacycles may involve
consecutive ring expansions of the respective optically active
lower homologue via the reaction with 1 as the methylenation
reagent. As this reaction proceeds via transition structure 2 and
intermediate betaine 3,28 leaving the stereogenic center un-
touched, complete retention of the configuration of the product
4 is expected (Scheme 1). This approach may be useful for the
construction of larger rings, i.e., the hitherto unknown methy-
lenation of oxetanes to oxolanes (n = 1).
(15) Balsamo, A.; Crotti, P.; Ferretti, M.; Macchia, F. J. Org. Chem.
1975, 40, 2870–2874.
(16) Bachki, A.; Falvello, L. R.; Foubelo, F.; Yus, M. Tetrahedron 1997,
8, 2633–2643.
(17) Nakata, T. Chem. Rev. 2005, 105, 4314–4347.
(18) Tang, Y. Q.; Sattler, I.; Thiericke, R.; Grabley, S.; Feng, X. Z.
J. Antibiot. 2000, 53, 934–943.
(19) Ishida, T.; In, Y.; Nishii, M.; Minami, Y. Chem. Lett. 1994, 1321–
1322.
As part of developing novel ylide chemistry53,54 we recently
demonstrated55 that upon the treatment of epoxides with an
excess of 1 small amounts of oxolanes form, demonstrating the
(20) Dillon, N. P.; Lee, N. C.; Stappenbeck, F.; White, J. D. J. Chem.
Soc., Chem. Comm. 1995, 1645–1646.
ꢀ
~
(21) de Vivar, A. R.; Perez, A.-L.; Arciniega, A.; Vidales, P.; Gavino, R.;
~
Villasenor, J. L. Tetrahedron 1995, 51, 12521–12528.
(22) Perez-Castorena, A. L.; Arciniegas, A.; Castro, A.; Villasenor, J. L.;
Toscano, R. A.; de Vivar, A. R. J. Nat. Prod. 1997, 60, 1322–1325.
(23) Chang, J.; Reiner, J.; Xie, J. Chem. Rev. 2005, 105, 4581–4609.
(24) Takao, K.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105, 4779–
4807.
(40) Bentley, P. A.; Bergeron, S.; Cappi, M. C.; Hibbs, D. E.; Hursthouse,
M. B.; Nugent, T. C.; Pulido, R.; Roberts, S. M.; Wu, L. E. J. Chem. Soc.,
Chem. Commun. 1997, 739–740.
(25) Welch, S. C.; Rao, A. S. C. P.; Lyon, J. T.; Assercq, J.-M. J. Am.
Chem. Soc. 1983, 105, 252–257.
(41) Porter, M. J.; Skidmore, J. J. Chem. Soc., Chem. Commun. 2000,
1215–1225.
(26) Sasaki, T.; Shimizu, K.; Masatomi, O. Chem. Pharm. Bull. 1984, 32,
1433–1440.
(27) Hintzer, K.; Koppenhoefer, B.; Schurig, V. J. Org. Chem. 1982, 47,
3850–3854.
(42) Lygo, B.; Wainwright, P. G. Tetrahedron 1999, 55, 6289–6300.
(43) Enders, D.; Hecker, P.; Meyer, O. Tetrahedron 1996, 52, 2909–2924.
(44) Enders, D.; Zhu, J.; Kramps, L. Liebigs Ann. Chem. 1997, 6, 1101–
1113.
(28) Okuma, K.; Tanaka, Y.; Kaji, S.; Ohta, H. J. Org. Chem. 1983, 48,
5133–5134.
(45) Elston, C. L.; Jackson, R. F. W.; Macdonald, S. J. F.; Murray, P. J.
Angew. Chem., Int. Ed. Engl. 1997, 36, 410–412.
(29) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–
5976.
(46) Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 2725–2732.
(30) Martin, V. S.; Woodward, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.;
Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237–6240.
(31) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224–11235.
(47) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.;
Porcelloni, M.; Studley, J. R. Angew. Chem., Int. Ed. 2001, 40, 1430–1433.
(48) Zanardi, J.; Leriverend, C.; Aubert, D.; Julienne, K.; Metzner, P.
J. Org. Chem. 2001, 41, 5620–5623.
(32) Wang, K.; Mayer, J. M. J. Org. Chem. 1997, 62, 4248–4252.
(33) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org.
Chem. 1998, 63, 2948–2953.
(49) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726–3748.
(50) Bertolini, F.; Crotti, S.; di Bussolo, V.; Macchia, F.; Pineschi, M.
J. Org. Chem. 2008, 73, 8998–9007.
(34) Shu, L.; Shen, Y.-M.; Burke, C.; Goeddel, D.; Shi, Y. J. Org. Chem.
2003, 68, 4963–4965.
(51) Sone, T.; Lu, G.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int.
Ed. 2009, 48, 1677–1680.
(35) Pirkle, V. H.; Rinaldi, P. L. J. Org. Chem. 1977, 42, 2080–2082.
(36) Ohta, H.; Tetsukawa, H. Agric. Biol. Chem. 1979, 43, 2099–2104.
(37) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J.-H.;
Cheung, K.-K. J. Am. Chem. Soc. 1996, 118, 491–492.
(38) Yang, D.; Wong, X.-C.; Wong, M.-K.; Yip, Y.-C.; Tang, M.-W.
J. Am. Chem. Soc. 1996, 118, 11311–11312.
(52) Sone, T.; Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2008, 130, 10078–10079.
(53) Kiriy, A. V.; Yurchenko, A. G.; Fokin, A. A. Zh. Org. Khim. 2002,
38, 471–472.
(54) Fokin, A. A.; Kushko, A. O.; Kirij, A. V.; Yurchenko, A. G.;
Schleyer, P. v. R. J. Org. Chem. 2000, 65, 2984–2995.
(55) Butova, E. D.; Fokin, A. A.; Schreiner, P. R. J. Org. Chem. 2007, 72,
5689–5696.
(39) Julia, S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed. Engl. 1980,
92, 968–969.
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SCHEME 2. Oxirane (5), Oxetane (7), and Oxolane (9) Ring Expansions with 1a
aRelative ΔH298 at MP2/6-31þG(d), PCM, DMSO in kcal mol-1, critical bond distances in A.
˚
feasibility of consecutive nucleophilic ring expansions with 1.
The synthetic potential as well as the mechanism and stereo-
chemistry of this transformation still remains unexplored. Here-
in we present experimental and computational results on the
consecutive expansions of cyclic ethers with 1 as the methylena-
tion agent. We have also studied experimentally the regio- and
stereospecificity of the epoxide and oxetane ring expansions with
1 to estimate their potential for the preparation of optically
active oxetanes and oxolanes.
carbonyl compounds.60 We used DMSO as the solvent for
both our computational modeling and the experiments. The
attack of 1 on oxirane (5, Scheme 2) through TS1 is asso-
ciated with a 17.5 kcal mol-1 barrier, which is in line with the
experimental observation that only moderate heating is
required;61 the gas phase computed barrier is much higher
(30.1 kcal mol-1). The ring opening is exothermic leading to
betaine 6; elimination of DMSO through low-energy TS2
gives oxetane (7). The ring expansion occurs via SN2-back-
side attack of 1 on the CH2-O fragment (the barrier for the
frontside attack is ca. 30.1 kcal mol-1 higher). Despite only a
small ring strain release,62 the overall transformation of 1 to
7 is highly exothermic (ΔH298 = -52.2 kcal mol-1). This large
driving force arises mainly from (i) the methylene transfer from
the ylide into the oxacycle and (ii) the large increase in solvation
energy in going from 1 to betaine 6. Indeed, the gas-phase
reaction (1 þ 5 f 6) is þ18.5 kcal mol-1 endothermic, em-
phasizing the importance of including the solvent in the
computations.
Results and Discussion
First we computed56 the consecutive ring expansions with
1 involving highly polarized transition structures and be-
taines. Since conventional gas-phase DFT and MP2 methods
overestimate the energies of such structures,57 we employed a
polarizable continuum model (PCM) to account for solvent
effects.58 This solvation model was previously successfully
used59 for the parent Corey-Chaykovsky reaction of 1 with
The barrier for the attack of 1 onto 7 increases by ca. 8 kcal
mol-1 (TS3); DMSO loss from betaine 8 through TS4 is a
fast process as both structures lie energetically below the
reactants. The ring expansion of oxolane 9 with formation of
(56) Frisch, M. J. et al. Gaussian, Inc.: Pittsburgh, PA, 2004. For the
details and the full reference see Supporting Information.
(57) Wei, Y.; Sateesh, B.; Maryasin, B.; Sastry, G. N.; Zipse, H.
J. Comput. Chem. 2009, 30, 2617–2624.
(58) Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55, 117–129.
(59) Aggarwal, V. K.; Harvey, J. N.; Richardson, J. J. Am. Chem. Soc.
2002, 124, 5747–5756.
(61) Okuma, K.; Tanaka, Y.; Kaji, S.; Ohta, H. J. Org. Chem. 1983, 48,
5133–5134.
(62) Stirling, C. J. M. Tetrahedron 1985, 41, 1613–1666.
(60) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353–
1364.
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FIGURE 1. Selected orbital diagrams and energies for TS1, TS3, and TS5.
the six-membered oxane ring 11 through betaine 10 and TS6
is hampered by the very large barriers for the initial attack
(TS5, 38.0 kcal mol-1). The results computed at MP2 deviate
only slightly from the DFT barriers, which are 18.9, 28.2, and
39.2 kcal mol-1 through TS1, TS3, and TS5, respectively
(PCM-B3PW91/6-31þG*).63
of 2-monosubstituted substrates. Thus, our computations
show that the ring expansions of oxacycles occur regioselec-
tively and stereospecifically.
To verify our computational findings experimentally, we
studied the methylenation of enantiopure (R)-2-phenyl- (14),
(R)-2-(n-hexyl)- (15), (R)-2-benzyloxymethyl- (16), (R)-2-
ethyl-2-phenyl- (17), and (2R,3R)-2-methyl-3-phenyl- (18)
oxiranes (Table 1, entries 1-5). The reactions proceed
smoothly in DMSO or tBuOH at 50-75 °C; 1 was prepared
in situ from dimethylsulfoxonium iodide and sodium hy-
dride or potassium tert-butylate (see Experimental Section
for details). As a result we observed full conservation of
the optical purity and retention of the stereochemistry was
observed for the resulting oxetanes 19-22 (Table 1). In
agreement with the computations the reactivity of 18 was
too low to study the stereochemistry of the ring expansion as
only trace amounts of product 23 were identified in the GC/
MS analysis (Table 1, entry 5).
Our computations show that the ring expansion of ox-
etane 7 to oxolane 9 is accompanied by a ca. 26 kcal mol-1
barrier. As a consequence, we were able to achieve satisfac-
tory conversions only upon heating to 125 °C. Oxetanes
24-32 were transformed to the respective oxolanes 33-41 in
56-91% preparative yields after 0.5-24 h representing a
new general oxetane ring expansion reaction (Table 2, entries
1-9). The resulting oxolanes are stable in the presence of 1;
this agrees well with the high barrier computed for the attack
of 1 onto 9 (Scheme 2).
Thus, computations indicate a substantial increase in the
barrier for the ring expansions of cyclic ethers from 5 to 7 and
to 9. This is due to decreasing contributions of the in-plane p-
orbitals to the bonding between the reactants in the HOMO-
2 of the transition structures TS1, TS3, and TS5 (Figure 1).
The overlap of these orbitals, that describes the newly
forming C-C bond, decreases with increase of the ring
size.
As expected, the methylenation of the epoxide ring is quite
sensitive to the substitution pattern. This is apparent from
the computations on the reaction of methyloxirane (12) with
1 (Scheme 3): the presence of the methyl group in 12 has no
influence on the barrier for the attack on the CH2 group
(TS7, 17.2 kcal mol-1, cf. TS1, 17.5 kcal mol-1, Scheme 2),
whereas the barrier for the attack on the tertiary carbon is
much higher (TS8, 21.6 kcal mol-1). Remarkably, in 2,2-
disubstituted oxirane (13) the presence of another alkyl
group decreases the barrier for the attack on the methylene
carbon by 1.6 kcal mol-1 (TS9) relative to monomethyl
derivative (TS7), presumably because of larger strain release
in TS9 versus TS7. As a consequence, the reactivity of 2,2-
disubstituted oxiranes toward 1 must be higher than that
We also tested the stereospecificity of the expansion of (S)-
2-phenyloxetane (19) and (S)-n-hexyloxetane (20) and
found complete conservation of the optical purity and
(63) We employed the method B3PW91, which is more trustworthy for
energy evaluations than other DFT methods (see Schreiner, P. R.; Fokin,
A. A.; Pascal, R. A.; A. de Meijere, Org. Lett. 2006, 8, 3635-3638).
6232 J. Org. Chem. Vol. 75, No. 18, 2010

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SCHEME 3. Relative Barriers for the Attack of 1 on 2-Methyl-(12) and 2,2-Dimethyloxirane (13)a
aRelative ΔH298 at MP2/6-31þG(d), PCM, DMSO in kcal mol-1, critical bond distances in A.
˚
TABLE 1. Ring Expansions of Optically Active Oxiranes with 1 in DMSO
aThe stereochemistry was determined through the optical rotations in combination with GC on optically active stationary phase (SiHydrodex β-6-
TBDM).
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TABLE 2. Ring Expansions of Oxetanes with 1 in Diglyme (120-
130 °C)
ca. 25 kcal mol-1 and take place at 120-130 °C to give
oxolanes in high preparative yields. Asymmetric epoxides
and oxetanes react with 1 regioselectively and stereospecifi-
cally. Full retention of enantiomeric purity and stereochem-
istry are observed for these nucleophilic ring expansions.
Thus, this represents a new and general method for the
preparation of optically active cyclic ethers from optically
pure epoxides. Oxolanes are stable even under prolonged
heating with 1 as the computed barriers for the ring expan-
sion to the six-membered oxanes are too high.
Experimental Section
General Procedures for Oxirane Ring Expansions. Procedure
A. To a well-stirred suspension of 0.038 g (1.6 mmol) of NaH in
dry DMSO (5 mL) was added 0.352 g (1.6 mmol) of trimethyl-
sulfoxonium iodide at room temperature. The mixture was
gently heated to 50-70 °C, and 2-hexyloxirane (1 mmol) in
DMSO (1 mL) was added in one portion. The reaction mixture
was stirred at that temperature for 24-48 h, cooled, carefully
quenched with water, and extracted three times with n-hexane.
The combined extracts were washed with water and brine and
dried over Na2SO4. Removal of the solvents gave the crude
product, whose purification by chromatography (Al2O3, penta-
ne-ether, 10:1) gave analytically pure oxetane 20 in 91%
preparative yield.
Procedure B. To a well-stirred suspension of 0.226 g (2 mmol)
of t-BuOK in dry t-BuOH (5 mL) was added 0.440 g (2 mmol) of
trimethylsulfoxonium iodide at room temperature. The mixture
was gently heated to 50-70 °C, and oxirane (1 mmol) in t-BuOH
(1 mL) was added in one portion. The reaction mixture was
stirred at that temperature for 15-72 h, cooled, carefully
quenched with water, and extracted three times with n-hexane.
The combined extracts were washed with water and brine and
dried over Na2SO4. Removal of the solvents gave an oil, further
purification as above gave pure oxetanes 19, 21, and 22 in
80-88% preparative yields (Table 1). The enantiomeric purity
(>98%) was determined on GC HP6890 with Hydrodex-β-
6TBDM stationary phase (25 m ꢀ 0.25 mm capillary column,
80-150 °C (1 °C/min), 150-250 °C (20 °C/min).
(S)-(-)-2-Phenyloxetane (19) through Procedure B64. 1H
NMR (CDCl3, δ, ppm): 2.48-2.70 (m, 1 H), 2.85-3.09 (m, 1
H), 4.52-4.68 (m, 1 H), 4.69-4.87 (m, 1 H), 5.76 (m, 1 H),
7.18-7.49 (m, 5 H). 13C NMR (CDCl3, δ, ppm): 30.7
(CH2), 68.3 (CH2), 82.9 (CH), 125.2 (CH), 127.8 (CH), 128.5
(CH), 143.6 (C). [R] D = -38.0° (c 0.0329, CHCl3). MS (m/z):
134 (12%), 104 (60%), 105 (100%), 106 (33%), 77 (40%), 51
(20%).
(R)-(þ)-n-Hexyloxetane (20) through Procedure A13. 1H
NMR (CDCl3, δ, ppm): 0.87 (t, J = 7 Hz, 3 H), 1.15-1.45 (m,
8 H), 1.52-1.58 (m, 2 H), 2.32 (m, 1 H), 2.62 (m, 1H), 4.50 (dt, 1H,
J = 6.0, J = 8.0 Hz), 4.64 (dt 1H, J = 6 Hz, J = 8 Hz), 4.85
(pentet, 1H J = 7 Hz). 13C NMR (CDCl3, δ, ppm): 14.6 (CH3),
23.2 (CH2), 24.6 (CH2), 28.0 (CH2), 29.8 (CH2), 32.4 (CH2), 38.6
(CH2), 68.6 (CH2), 83.4 (CH). [R]D = þ9.17° (c 0.0287 g/mL,
CHCl3). MS (m/z): 124 (7%), 113 (5%), 95 (10%), 81 (25%), 71
(100%), 67 (25%), 57 (20%), 55 (40%), 53 (5%).
aThe stereochemistry was determined through the optical rotations in
combination with GC on optically active stationary phase (SiHydrodex
β-6-TBDM).
stereochemistry of resulting oxolanes (S)- and (R)-42 and
(S)-43 (Table 2, entries 10 and 11).
(R)-(þ)-2-Benzyloxymethyloxetane (21) through Procedure B65.
1H NMR (CDCl3, δ, ppm): 2.45-2.62 (m, 2 H), 3.23-3.60 (m, 2
H), 4.43-4.61 (m, 2 H), 4.51 (s, 2 H), 4.86-4.93 (m, 1 H),
7.12-7.29 (m, 5 H). 13C NMR (CDCl3, δ, ppm): 23.9 (CH2),
70.0 (CH2), 73.4 (CH2), 73.5 (CH2), 81.2 (CH), 127.6 (CH), 127.7
(CH), 128.4 (CH), 138.3 (C). [R]D = þ4.7° (c 0.0090 g/mL,
Conclusions
The methylenations of oxacycles with 1 occur via SN2-type
transition structures and are accompanied by fast elimi-
nation of DMSO. The expansion of the oxirane ring is
associated with barriers of 15-17 kcal mol-1, thus requiring
only moderate heating; 2-alkyl- and 2,2-dialkyloxiranes
are similarly reactive. The oxetane ring expansions require
(64) Lo, M. M.-C.; Fu, G. C. Tetrahedron 2001, 57, 2621–2634.
(65) Chakraborty, T. K.; Hussain, A. K.; Joshi, S. P. Chem. Lett. 1992, 12,
2385–2388.
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Butova et al.
JOCArticle
CHCl3). MS (m/z): 178 (1%), 107 (65%), 105 (20%), 92 (20%), 91
(100%), 79 (24%), 65 (35%), 57 (75%), 51 (24%).
(CH2), 38.3 (CH2), 67.2 (CH2), 84.9 (C). MS (m/z): 127 (100%),
85 (26%), 57 (58%).
(S)-(-)-2-Ethyl-2-phenyloxetane (22) through Procedure B51.
1H NMR (CDCl3, δ, ppm): 0.84 (m, 3 H), 1.79-2.20 (m, 2 H),
2,2-Diphenyloxolane (38)70. 1H NMR (CDCl3, δ, ppm): 1.76-
2.00 (m, 2 H), 2.44 (t, J = 11 Hz 2 H), 3.92 (t, J = 11 Hz, 2 H),
7.04-7.46 (m, 10 H). 13C NMR (CDCl3, δ, ppm): 25.6 (CH2),
38.7 (CH2), 67.5 (CH2), 88.1 (C), 125.9 (CH), 126.85 (CH),
128.4 (CH), 146.6 (C). MS (m/z): 224 (56%), 165 (15%), 148
(15%), 147 (98%), 115 (18%), 105 (100%), 91 (14%), 77 (70%),
51 (24%).
2.60-2.96 (m, 2 H), 4.41-4.68 (m, 2 H), 7.16-7.49 (m, 5 H). 13
C
NMR (CDCl3, δ, ppm): 7.5 (CH3), 33.3 (CH2), 36.0 (CH2), 65.0
(CH2), 89.3 (C), 124.2 (CH), 126.5 (CH), 128.0 (CH), 146.8 (C).
[R]D = -63.1° (c 0.0169 g/mL, CHCl3). MS (m/z): 162 (7%), 132
(25%), 117 (45%), 105 (50%), 91 (45%), 77 (80%), 51 (100%).
General Procedure for Oxetane Ring Expansions. To a well-
stirred suspension of 0.24 g (10 mmol) of NaH in dry diglyme
(5 mL) was added 1.32 g (6 mmol) of trimethylsulfoxonium
iodide at room temperature. The mixture was gently heated to
120-130 °C, and 1 mmol of oxetane in diglyme (1 mL) was
added in one portion. The reaction mixture was stirred at
120-130 °C for 0.5-20 h, cooled, carefully quenched with
water, and extracted three times with n-hexane. The combined
extracts were washed with water and brine and dried over
Na2SO4. Removal of solvent and purification by chromatogra-
phy on silica gel (pentane-ether, 8:1) gave the respective
oxolanes 33-43, in 56-84% preparative yields (Table 2).
1-Oxaspiro[4.6]undecane (39). Identical to the standard sam-
ple obtained earlier.55
1-Oxaspiro[4.11]hexadecane (40)71. Colorless liquid. 1H NMR
(CDCl3, δ, ppm): 1.27 (bs, 20 H), 1.46-1.62 (m, 4 H), 1.68-1.93
(m, 2 H), 3.70 (t, J = 8 Hz, 2 H). 13C NMR (CDCl3, δ, ppm): 20.1
(CH2), 22.2 (CH2), 22.5 (CH2), 25.6 (CH2), 26.1 (CH2), 26.6
(CH2), 33.1 (CH2), 36.1 (CH2), 66.4 (CH2), 85.5 (C). MS (m/z):
224 (7%), 97 (100%), 84 (64%), 55 (43%). HRMS (m/z): found
224.2140; calcd for C15H28O 224.2143.
7-tert-Butyl-1-oxaspiro[4.5]decane (41)72. Colorless liquid. 1H
NMR (CDCl3, δ, ppm): 0.8 (s, 9 H), 1.21-1.30 (m, 4 H),
1.49-1.58 (m, 5 H), 1.65-1.71 (m, 2 H), 1.77-1.86 (m, 2 H),
3.73 (t, J = 8 Hz, 2 H). 13C NMR (CDCl3, δ, ppm): 23.8 (CH2),
25.4 (CH2), 27.7 (CH3), 32.4 (C), 37.1 (CH2), 38.2 (CH2), 47.8
(CH), 66.7 (CH2), 80.9 (C). MS (m/z): 196 (6%), 97 (100%), 84
(15%), 55 (25%). HRMS (m/z): found 196.1828; calcd for
C13H24O 196.1827.
2-Methyl-2-phenyloxolane (33)66,67 1H NMR (CDCl3, δ,
.
ppm): 1.50 (s, 3 H), 1.68-2.31 (m, 4 H), 3.83-4.10 (m, 2 H),
7.17-7.43 (m, 5 H). 13C NMR (CDCl3, δ, ppm): 25.8 (CH2),
29.7 (CH3), 39.5 (CH2), 67.6 (CH2), 84.3 (C), 124.7 (CH), 126.3
(CH), 128.1 (CH), 148.2 (C). MS (m/z): 162 (1%), 147 (100%),
105 (90%), 91 (18%), 77 (54%), 51 (20%).
1
(S)-(-)-2-Phenyloxolane (42)73. H NMR (CDCl3, δ, ppm):
2-Methyl-2-(4-methylphenyl)oxolane (34). Colorless liquid.
1H NMR (CDCl3, δ, ppm): 1.44 (s, 3 H), 1.60- 2.20 (m, 4 H),
2.25 (s, 3 H), 3.72-4.03 (m, 2 H), 7.00-7.10 (m, 2 H), 7.15-7.25
(m, 2 H). 13C NMR (CDCl3, δ, ppm): 21.0 (CH3), 25.8 (CH2),
29.8 (CH3), 39.4 (CH2), 67.5 (CH2), 84.1 (C), 124.6 (CH), 128.7
(CH), 135.8 (C), 145.1 (C). MS (m/z) 176 (5%), 161 (100%), 119
(98%), 91 (48%), 65 (24%), 51 (13%). HRMS (m/z): found
176.1203; calcd for C12H16O 176.1201.
1.68-1.85 (m, 1 H), 1.9 -2.11 (m, 2 H), 2.22-2.34 (m, 1 H),
3.85-3.90 (m, 1 H), 4.00-4.07 (m, 1 H), 4.88-4.91 (m, 1 H),
7.2-7.4 (m, 5 H). 13C NMR (CDCl3, δ, ppm): 26.1 (CH2), 34.7
(CH2), 68.7 (CH2), 80.7 (CH), 125.7 (CH), 127.1 (CH), 128.3
(CH), 143.5 (C). MS (m/z): 148 (78%), 147 (100%), 117 (15%),
105 (80%), 91 (12%), 77 (20%); [R]D = -37.6°, (c 0.0162 g/mL,
CHCl3). The enantiomeric purity (>98%) was determined on
GC HP6890 with Hydrodex-β-6TBDM stationary phase (25 m
ꢀ 0.25 mm capillary column, 80-150 °C (1 °C/min), 150-
250 °C (20 °C/min). (R)-(þ)-2-Phenyloxolane (42): yield 85%.
[R]D = þ40.7° ( c 0.0142 g/mL, CHCl3).
1
2-(4-Fluorophenyl)oxolane (35)68. H NMR (CDCl3, δ, ppm):
1.65-1.78 (m, 1 H), 1.86-2.03 (m, 2 H), 2.16-2.31 (m, 1 H),
3.79-3.92 (m, 1 H), 3.98-4.07 (m, 1 H), 4.76-4.84 (m, 1 H),
6.89-7.02 (m, 2H), 7.16 - 7.28 (m, 2 H). 13C NMR (CDCl3, δ,
ppm): 26.0 (CH2), 34.7 (CH2), 68.6 (CH2), 80.1 (CH), 115.0 (d,
J = 21 Hz, CH), 127.2 (d, J = 8 Hz, CH), 139.0 (d, J = 2 Hz, C),
162.0 (d, J = 234 Hz, C). 19F NMR (CDCl3, δ, ppm, CBr2F2):
-115.9 (s). MS (m/z): 166 (23%), 165 (30%), 123 (100%), 109
(40%), 95 (67%), 75 (60%), 50 (40%).
(R)-(þ)-n-Hexyloxolane (43)70. 1H NMR: 0.81-0.91 (m,
3 H), 1.15-1.48 (m, 11 H), 1.77-2.08 (m, 3H, 3.62-3.94 (m, 3
H). 13C NMR: 14.1 (CH3), 22.6 (CH2), 25.7 (CH2), 26.4 (CH2),
29.4 (CH2), 31.4 (CH2), 31.9 (CH2), 35.8 (CH2), 67.7 (CH2), 79.5
(CH); [R]D =þ 3.98°, (c 0.0061 g/mL, CHCl3). MS (m/z): 156
(<1%), 138, 71 (100%). The enantiomeric purity (>98%)
was determined on GC HP6890 with Hydrodex-β-6TBDM
stationary phase (25 m x 0.25 mm capillary column, 80-150 °C
(1 °C/min), 150-250 °C (20 °C/min).
1
2-Methyl-2-naphtyloxolane (36). Colorless liquid. H NMR
(CDCl3, δ, ppm): 1.44 (s, 3 H), 1.62-2.36 (m, 4 H), 3.82-4.10
(m, 2 H), 7.29-7.50 (m, 3 H), 7.65-7.87 (m, 4 H). 13C NMR
(CDCl3, δ, ppm): 25.8 (CH2), 29.6 (CH3), 39.4 (CH2), 67.7
(CH2), 84.40 (C), 122.9 (CH), 123.8 (CH), 125.5 (CH), 126.0
(CH), 127.5 (CH), 127.9 (CH), 128.1 (CH), 132.3 (C), 133.2 (C),
145.5 (C). MS (m/z):212(21%), 197(100%),155(75%), 127(60%).
HRMS (m/z): found 212.1206; calcd for C15H16O 212.1201.
Acknowledgment. This work was supported by the Deutsche
Forschungsgemeinschaft, the Ministry of Science and Education
of the Ukraine, and the Fonds der Chemischen Industrie.
2,2-Di-n-butyloxolane (37)69. 1H NMR (CDCl3, δ, ppm):
0.85-0.93 (m, 6 H), 1.04-1.50 (m, 12 H), 1.51-1.68 (m, 2 H),
1.70-1.90 (m, 2 H), 3.72 (t, J = 7 Hz, 2 H). 13C NMR (CDCl3, δ,
ppm): 14.1 (CH3), 23.4 (CH2), 26.3 (CH2), 26.6 (CH2), 35.1
Supporting Information Available: Copies of the NMR
spectra, description of the theoretical methods, and XYZ co-
ordinates of optimized species. This material is available free of
charge via the Internet at http://pubs.acs.org.
(66) Frank, X.; Figadere, B.; Cave, A. Tetrahedron Lett. 1997, 38, 1413–
1414.
(67) Hartung, J.; Schwarz, M.; Svoboda, I.; Fuess, H.; Duarte, M. T.
Eur. J. Org. Chem. 1999, 1275–1290.
(68) Hanson, R. L.; Banerjee, A.; Taha Comezoglu, F.; David Mirfakhrae,
K.; Patel, R. N.; Szarka, L. J. Tetrahedron: Asymmetry 1994, 5, 1925–1934.
(69) Fukuzawa, S.; Furuya, H.; Tsuchimoto, T. Tetrahedron 1953, 52,
1953–1960.
(70) Hansen, M. C.; Verdaguer, X.; Buchwald, S. L. J. Org. Chem. 1998,
63, 2360–2361.
(71) Weyerstahl, P.; Brendel, J.; Lutz, G. Flavour Fragrance J. 1992, 7,
1–7.
(72) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S. J. Chem. Soc.,
Perkin Trans. 1 1988, 1669–1675.
(73) Pirkle, W. H.; Spence, P. L. J. Chromatogr., A 1997, 775, 81–90.
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